Unravelling the mechanisms regulating muscle mitochondrial biogenesis

Biochemical Journal

Volumn 473, Issue 15, 2016, Pages 2295-2314

  Hood, David A ^a   Tryon, Liam D ^a   Carter, Heather N ^a   Kim, Yuho ^a   Chen, Chris C W ^a  

^a YORK UNIVERSITY   (Canada)

Author keywords

(PGC 1 ); mtDNA; Aging; Calcium signalling; Co activator 1 ; Exercise; Exercise training; Mitochondrial protein import; Mitochondrial reticulum; Mitophagy; Muscle disuse; P53; PPAR ; Reactive oxygen species; Tfam; Tfeb

Indexed keywords

MITOCHONDRIAL PROTEIN; MITOCHONDRIAL TRANSCRIPTION FACTOR A; NICOTINAMIDE ADENINE DINUCLEOTIDE; PROTEIN P53; RESVERATROL; TRANSCRIPTION FACTOR; [2 METHYL 4 [4 METHYL 2 (4 TRIFLUOROMETHYLPHENYL) 5 THIAZOLYLMETHYLTHIO]PHENOXY]ACETIC ACID; TRANSACTIVATOR PROTEIN;

AGING; BIOGENESIS; CELL ORGANELLE; EXERCISE; HEALTH; MITOCHONDRIAL BIOGENESIS; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL GENOME; MITOCHONDRION; MITOPHAGY; MORPHOLOGY; MUSCLE MASS; MUSCLE MITOCHONDRION; PRECURSOR; PRIORITY JOURNAL; REVIEW; SKELETAL MUSCLE; ANIMAL; HUMAN; METABOLISM; ORGANELLE BIOGENESIS; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION;

AGING; ANIMALS; EXERCISE; HUMANS; MITOCHONDRIA, MUSCLE; MITOCHONDRIAL PROTEINS; MUSCLE, SKELETAL; ORGANELLE BIOGENESIS; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION; TRANS-ACTIVATORS;

EID: 85009394793     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BCJ20160009     Document Type: Review

References (324)

1. Hoppeler, H. (1986) Exercise-induced ultrastructural changes in skeletal muscle. Int. J. Sports Med. 7, 187-204 CrossRef PubMed
2. Kelley, D. E., He, J., Menshikova, E. V. and Ritov, V. B. (2002) Dysfunction of mitochondria in human skeletal muscle in Type 2 diabetes. Diabetes 51, 2944-2950 CrossRef PubMed
3. Tryon, L. D., Vainshtein, A., Memme, J. M., Crilly, M. J. and Hood, D. A. (2014) Recent advances in mitochondrial turnover during chronic muscle disuse. Integr. Med. Res. 3, 161-171 CrossRef
4. Lin, M. T. and Beal, M. F. (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795 CrossRef PubMed
5. Carter, H. N., Chen, C. C. W. and Hood, D. A. (2015) Mitochondria, muscle health, and exercise with advancing age. Physiology 30, 208-223 CrossRef PubMed
6. Romanello, V. and Sandri, M. (2016) Mitochondrial quality control and muscle mass maintenance. Front. Physiol. 6, 1-21 CrossRef
7. Adhihetty, P. J., Uguccioni, G., Leick, L., Hidalgo, J., Pilegaard, H. and Hood, D. A. (2009) The role of PGC-1alpha on mitochondrial function and apoptotic susceptibility in muscle. Am. J. Physiol. Cell Physiol. 297, C217-C225 CrossRef PubMed
8. Saleem, A., Adhihetty, P. J. and Hood, D. A. (2009) Role of p53 in mitochondrial biogenesis and apoptosis in skeletal muscle. Physiol. Genomics 37, 58-66 CrossRef PubMed
9. Carter, H. N. and Hood, D. A. (2012) Contractile activity-induced mitochondrial biogenesis and mTORC1. Am. J. Physiol. Cell Physiol. 303, C540-C547 CrossRef PubMed
10. Menzies, K. J., Singh, K., Saleem, A. and Hood, D. A. (2013) Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J. Biol. Chem. 288, 6968-6979 CrossRef PubMed
11. Holloszy, J. O. (1967) Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J. Biol. Chem. 242, 2278-2282 PubMed
12. Ljubicic, V., Adhihetty, P. J. and Hood, D. A. (2005) Application of animal models: chronic electrical stimulation-induced contractile activity. Can. J. Appl. Physiol. 30, 625-643 CrossRef PubMed
13. Pette, D., Smith, M. E., Staudte, H. W. and Vrbová, G. (1973) Effects of long-term electrical stimulation on some contractile and metabolic characteristics of fast rabbit muscles. Pflügers Arch. 338, 257-272 CrossRef
14. Connor, M. K., Irrcher, I. and Hood, D. A. (2001) Contractile activity-induced transcriptional activation of cytochrome c involves Sp1 and is proportional to mitochondrial ATP synthesis in C2C12 muscle cells. J. Biol. Chem. 276, 15898-15904 CrossRef PubMed
15. Irrcher, I. and Hood, D. A. (2004) Regulation of Egr-1, SRF, and Sp1 mRNA expression in contracting skeletal muscle cells. J. Appl. Physiol. 97, 2207-2213 CrossRef PubMed
16. Uguccioni, G. and Hood, D. A. (2011) The importance of PGC-1 in contractile activity-induced mitochondrial adaptations. Am. J. Physiol. Endocrinol. Metab. 300, E361-E371 CrossRef PubMed
17. Raschke, S., Eckardt, K., Bjørklund Holven, K., Jensen, J. and Eckel, J. (2013) Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. PLoS One 8, e62008 CrossRef PubMed
18. Nedachi, T., Fujita, H. and Kanzaki, M. (2008) Contractile C2C12 myotube model for studying exercise-inducible responses in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 295, E1191-E1204 CrossRef PubMed
19. Burch, N., Arnold, A.-S., Item, F., Summermatter, S., Brochmann Santana Santos, G., Christe, M., Boutellier, U., Toigo, M. and Handschin, C. (2010) Electric pulse stimulation of cultured murine muscle cells reproduces gene expression changes of trained mouse muscle. PLoS One 5, e10970 CrossRef PubMed
20. Manabe, Y., Miyatake, S., Takagi, M., Nakamura, M., Okeda, A., Nakano, T., Hirshman, M. F., Goodyear, L. J. and Fujii, N. L. (2012) Characterization of an acute muscle contraction model using cultured C2C12 myotubes. PLoS One 7, e52592 CrossRef PubMed
21. Iqbal, S. and Hood, D. A. (2014) Cytoskeletal regulation of mitochondrial movements in myoblasts. Cytoskeleton 71, 564-572 CrossRef PubMed
22. Iqbal, S. and Hood, D. A. (2014) Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts. Am. J. Physiol. Cell Physiol. 306, C1176-C1183 CrossRef PubMed
23. O'Leary, M. F. N., Vainshtein, A., Carter, H. N., Zhang, Y. and Hood, D. A. (2012) Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals. Am. J. Physiol. Cell Physiol. 303, C447-C454 CrossRef PubMed
24. Kirkwood, S. P., Munn, E. A. and Brooks, G. A. (1986) Mitochondrial reticulum in limb skeletal muscle. Am. J. Physiol. 20, C395-C402
25. Ogata, T. and Yamasaki, Y. (1985) Scanning electron-microscopic studies on the three-dimensional structure of sarcoplasmic reticulum in the mammalian red, white and intermediate muscle fibers. Cell Tissue Res. 241, 251-256 CrossRef PubMed
26. Picard, M., White, K. and Turnbull, D. M. (2013) Mitochondrial morphology, topology, and membrane interactions in skeletal muscle: a quantitative three-dimensional electron microscopy study. J. Appl. Physiol. 114, 161-171 CrossRef PubMed
27. Glancy, B., Hartnell, L. M., Malide, D., Yu, Z.-X., Combs, C. A., Connelly, P. S., Subramaniam, S. and Balaban, R. S. (2015) Mitochondrial reticulum for cellular energy distribution in muscle. Nature 523, 617-620 CrossRef PubMed
28. Pette, D. and Hofer, H. W. (1980) The constant proportion enzyme group concept in the selection of reference enzymes in metabolism. Ciba Found. Symp. 73, 231-242
29. Reichmann, H., Hoppeler, H., Mathieu-Costello, O., von Bergen, F. and Pette, D. (1985) Biochemical and ultrastructural changes of skeletal muscle mitochondria after chronic electrical stimulation in rabbits. Pflügers Arch. 404, 1-9 CrossRef
30. Williams, R. S. (1986) Mitochondrial gene expression in mammalian striated muscle. Evidence that variation in gene dosage is the major regulatory event. J. Biol. Chem. 261, 12390-12394 PubMed
31. Osman, C., Voelker, D. R. and Langer, T. (2011) Making heads or tails of phospholipids in mitochondria. J. Cell Biol. 192, 7-16 CrossRef PubMed
32. Takahashi, M. and Hood, D. A. (1993) Chronic stimulation-induced changes in mitochondria and performance in rat skeletal muscle. J. Appl. Physiol. 74, 934-941 PubMed
33. Wicks, K. L. and Hood, D. A. (1991) Mitochondrial adaptations in denervated muscle: relationship to muscle performance. Am. J. Physiol. 260, C841-C850 PubMed
34. Ostojic, O., O'Leary, M. F. N., Singh, K., Menzies, K. J., Vainshtein, A. and Hood, D. A. (2013) The effects of chronic muscle use and disuse on cardiolipin metabolism. J. Appl. Physiol. 114, 444-452 CrossRef PubMed
35. Rooyackers, O. E., Adey, D. B., Ades, P. A. and Nair, K. S. (1996) Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proc. Natl. Acad. Sci. U. S. A. 93, 15364-15369 CrossRef PubMed
36. Connor, M. K., Bezborodova, O., Escobar, C. P. and Hood, D. A. (2000) Effect of contractile activity on protein turnover in skeletal muscle mitochondrial subfractions. J. Appl. Physiol. 88, 1601-1606 PubMed
37. Wilkinson, S. B., Phillips, S. M., Atherton, P. J., Patel, R., Yarasheski, K. E., Tarnopolsky, M. A. and Rennie, M. J. (2008) Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle. J. Physiol. 586, 3701-3717 CrossRef PubMed
38. Di Donato, D. M., West, D. W. D., Churchward-Venne, T. A., Breen, L., Baker, S. K. and Phillips, S. M. (2014) Influence of aerobic exercise intensity on myofibrillar and mitochondrial protein synthesis in young men during early and late postexercise recovery. Am. J. Physiol. Endocrinol. Metab. 306, E1025-E1032 CrossRef PubMed
39. Miller, B. F., Robinson, M. M., Bruss, M. D., Hellerstein, M. and Hamilton, K. L. (2012) A comprehensive assessment of mitochondrial protein synthesis and cellular proliferation with age and caloric restriction. Aging Cell 11, 150-161 CrossRef PubMed
40. Cogswell, A. M., Stevens, R. J. and Hood, D. A. (1993) Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Am. J. Physiol. 264, C383-C389 PubMed
41. Perry, C. G. R., Kane, D. A., Lanza, I. R. and Neufer, P. D. (2013) Methods for assessing mitochondrial function in diabetes. Diabetes 62, 1041-1053 CrossRef PubMed
42. Klionsky, D. J. (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1-222 CrossRef PubMed
43. Puigserver, P., Adelmant, G., Wu, Z., Fan, M., Xu, J., O'Malley, B. and Spiegelman, B. M. (1999) Activation of PPARgamma coactivator-1 through transcription factor docking. Science 286, 1368-1371 CrossRef PubMed
44. Wallberg, A. E., Yamamura, S., Malik, S., Spiegelman, B. M. and Roeder, R. G. (2003) Coordination of p300-mediated chromatin remodeling and TRAP/Mediator function through coactivator PGC-1. Mol. Cell 12, 1137-1149 CrossRef PubMed
45. Scarpulla, R. C. (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269-1278 CrossRef PubMed
46. Scarpulla, R. C., Vega, R. B. and Kelly, D. P. (2012) Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459-466 CrossRef PubMed
47. Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M. and Spiegelman, B. M. (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829-839 CrossRef PubMed
48. Calvo, J. A., Daniels, T. G., Wang, X., Paul, A., Lin, J., Spiegelman, B. M., Stevenson, S. C. and Rangwala, S. M. (2008) Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake. J. Appl. Physiol. 104, 1304-1312 CrossRef PubMed
49. Sonoda, J., Mehl, I. R., Chong, L.-W., Nofsinger, R. R. and Evans, R. M. (2007) PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc. Natl. Acad. Sci. U. S. A. 104, 5223-5228 CrossRef PubMed
50. Lelliott, C. J., Medina-Gomez, G., Petrovic, N., Kis, A., Feldmann, H. M., Bjursell, M., Parker, N., Curtis, K., Campbell, M., Hu, P. et al. (2006) Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol. 4, e369 CrossRef PubMed
51. Lin, J., Wu, P.-H., Tarr, P. T., Lindenberg, K. S., St-Pierre, J., Zhang, C.-Y., Mootha, V. K., Jäger, S., Vianna, C. R., Reznick, R. M. et al. (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119, 121-135 CrossRef PubMed
52. Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N. K., Yan, Z. and Spiegelman, B. M. (2007) Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J. Biol. Chem. 282, 30014-30021 CrossRef PubMed
53. Gali Ramamoorthy, T., Laverny, G., Schlagowski, A.-I., Zoll, J., Messaddeq, N., Bornert, J.-M., Panza, S., Ferry, A., Geny, B. and Metzger, D. (2015) The transcriptional coregulator PGC-1 controls mitochondrial function and anti-oxidant defence in skeletal muscles. Nat. Commun. 6, 10210 CrossRef PubMed
54. Handschin, C., Choi, C. S., Chin, S., Kim, S., Kawamori, D., Kurpad, A. J., Neubauer, N., Hu, J., Mootha, V. K., Kim, Y.-B. et al. (2007) Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J. Clin. Invest. 117, 3463-3474 CrossRef PubMed
55. Zechner, C., Lai, L., Zechner, J. F., Geng, T., Yan, Z., Rumsey, J. W., Collia, D., Chen, Z., Wozniak, D. F., Leone, T. C. and Kelly, D. P. (2010) Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab. 12, 633-642 CrossRef PubMed
56. Rowe, G. C., Patten, I. S., Zsengeller, Z. K., El-Khoury, R., Okutsu, M., Bampoh, S., Koulisis, N., Farrell, C., Hirshman, M. F., Yan, Z. et al. (2013) Disconnecting mitochondrial content from respiratory chain capacity in PGC-1-deficient skeletal muscle. Cell Rep. 3, 1449-1456 CrossRef PubMed
57. Baar, K., Wende, A. R., Jones, T. E., Marison, M., Nolte, L. A., Chen, M., Kelly, D. P. and Holloszy, J. O. (2002) Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 16, 1879-1886 CrossRef PubMed
58. Irrcher, I., Adhihetty, P. J., Sheehan, T., Joseph, A. M. and Hood, D. A. (2003) PPARγ coactivator-1 expression during thyroid hormone-and contractile activity-induced mitochondrial adaptations. Am. J. Physiol. Cell Physiol. 284, C1669-C1677 CrossRef PubMed
59. Zhang, Y., Uguccioni, G., Ljubicic, V., Irrcher, I., Iqbal, S., Singh, K., Ding, S. and Hood, D. A. (2014) Multiple signaling pathways regulate contractile activity-mediated PGC-1 gene expression and activity in skeletal muscle cells. Physiol. Rep. 2, 1-12
60. Pilegaard, H., Saltin, B. and Neufer, P. D. (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J. Physiol. 546, 851-858 CrossRef PubMed
61. Akimoto, T., Pohnert, S. C., Li, P., Zhang, M., Gumbs, C., Rosenberg, P. B., Williams, R. S. and Yan, Z. (2005) Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J. Biol. Chem. 280, 19587-19593 CrossRef PubMed
62. Akimoto, T., Li, P. and Yan, Z. (2008) Functional interaction of regulatory factors with the Pgc-1alpha promoter in response to exercise by in vivo imaging. Am. J. Physiol. Cell Physiol. 295, C288-C292 CrossRef PubMed
63. Wright, D. C., Han, D. H., Garcia-Roves, P. M., Geiger, P. C., Jones, T. E. and Holloszy, J. O. (2007) Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J. Biol. Chem. 282, 194-199 CrossRef PubMed
64. Vainshtein, A., Tryon, L. D., Pauly, M. and Hood, D. A. (2015) Role of PGC-1 during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am. J. Physiol. Cell Physiol. 308, C710-C719 CrossRef PubMed
65. Handschin, C., Rhee, J., Lin, J., Tarr, P. T. and Spiegelman, B. M. (2003) An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc. Natl. Acad. Sci. U. S. A. 100, 7111-7116 CrossRef PubMed
66. Leick, L., Wojtaszewski, J. F. P., Johansen, S. T., Kiilerich, K., Comes, G., Hellsten, Y., Hidalgo, J. and Pilegaard, H. (2008) PGC-1alpha is not mandatory for exercise-and training-induced adaptive gene responses in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 294, E463-E474 CrossRef PubMed
67. Rowe, G. C., El-Khoury, R., Patten, I. S., Rustin, P. and Arany, Z. (2012) PGC-1 is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle. PLoS One 7, e41817 CrossRef PubMed
68. Miura, S., Kawanaka, K., Kai, Y., Tamura, M., Goto, M., Shiuchi, T., Minokoshi, Y. and Ezaki, O. (2007) An increase in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to exercise is mediated by beta-adrenergic receptor activation. Endocrinology 148, 3441-3448 CrossRef PubMed
69. Miura, S., Kai, Y., Kamei, Y. and Ezaki, O. (2008) Isoform-specific increases in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to beta2-adrenergic receptor activation and exercise. Endocrinology 149, 4527-4533 CrossRef PubMed
70. Chinsomboon, J., Ruas, J., Gupta, R. K., Thom, R., Shoag, J., Rowe, G. C., Sawada, N., Raghuram, S. and Arany, Z. (2009) The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle. Proc. Natl. Acad. Sci. U. S. A. 106, 21401-21406 CrossRef PubMed
71. Yoshioka, T., Inagaki, K., Noguchi, T., Sakai, M., Ogawa, W., Hosooka, T., Iguchi, H., Watanabe, E., Matsuki, Y., Hiramatsu, R. et al. (2009) Identification and characterization of an alternative promoter of the human PGC-1alpha gene. Biochem. Biophys. Res. Commun. 381, 537-543 CrossRef PubMed
72. Correia, J. C., Ferreira, D. M. S. and Ruas, J. L. (2015) Intercellular: local and systemic actions of skeletal muscle PGC-1s. Trends Endocrinol. Metab. 26, 305-314 CrossRef PubMed
73. Martínez-Redondo, V., Pettersson, A. T. and Ruas, J. L. (2015) The hitchhiker's guide to PGC-1 isoform structure and biological functions. Diabetologia 58, 1969-1977 CrossRef PubMed
74. Zhang, Y., Huypens, P., Adamson, A. W., Chang, J. S., Henagan, T. M., Boudreau, A., Lenard, N. R., Burk, D., Klein, J., Perwitz, N. et al. (2009) Alternative mRNA splicing produces a novel biologically active short isoform of PGC-1alpha. J. Biol. Chem. 284, 32813-32826 CrossRef PubMed
75. Ruas, J. L., White, J. P., Rao, R. R., Kleiner, S., Brannan, K. T., Harrison, B. C., Greene, N. P., Wu, J., Estall, J. L., Irving, B. A. et al. (2012) A PGC-1 isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151, 1319-1331 CrossRef PubMed
76. Silvennoinen, M., Ahtiainen, J. P., Hulmi, J. J., Pekkala, S., Taipale, R. S., Nindl, B. C., Laine, T., Häkkinen, K., Selänne, H., Kyröläinen, H. and Kainulainen, H. (2015) PGC-1 isoforms and their target genes are expressed differently in human skeletal muscle following resistance and endurance exercise. Physiol. Rep. 3, e12563 PubMed
77. Ogborn, D. I., McKay, B. R., Crane, J. D., Safdar, A., Akhtar, M., Parise, G. and Tarnopolsky, M. A. (2015) Effects of age and unaccustomed resistance exercise on mitochondrial transcript and protein abundance in skeletal muscle of men. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R734-R741 CrossRef PubMed
78. Ydfors, M., Fischer, H., Mascher, H., Blomstrand, E., Norrbom, J. and Gustafsson, T. (2013) The truncated splice variants, NT-PGC-1 and PGC-14, increase with both endurance and resistance exercise in human skeletal muscle. Physiol. Rep. 1, e00140 CrossRef PubMed
79. Schudt, C., Gaertner, U., Dölken, G. and Pette, D. (1975) Calcium-related changes of enzyme activities in energy metabolism of cultured embryonic chick myoblasts and myotubes. Eur. J. Biochem. 60, 579-586 CrossRef PubMed
80. Freyssenet, D., Irrcher, I., Connor, M. K., Di Carlo, M. and Hood, D. A. (2004) Calcium-regulated changes in mitochondrial phenotype in skeletal muscle cells. Am. J. Physiol. Cell Physiol. 286, C1053-C1061 CrossRef PubMed
81. Ojuka, E. O., Jones, T. E., Han, D. H., Chen, M. and Holloszy, J. O. (2003) Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle. FASEB J. 17, 675-681 CrossRef PubMed
82. Wu, H., Kanatous, S. B., Thurmond, F. A., Gallardo, T., Isotani, E., Bassel-Duby, R. and Williams, R. S. (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296, 349-352 CrossRef PubMed
83. Freyssenet, D., Di Carlo, M. and Hood, D. A. (1999) Calcium-dependent regulation of cytochrome c gene expression in skeletal muscle cells: identification of a protein kinase c-dependent pathway. J. Biol. Chem. 274, 9305-9311 CrossRef PubMed
84. Chin, E. R., Grange, R. W., Viau, F., Simard, A. R., Humphries, C., Shelton, J., Bassel-Duby, R., Williams, R. S. and Michel, R. N. (2003) Alterations in slow-twitch muscle phenotype in transgenic mice overexpressing the Ca2+ buffering protein parvalbumin. J. Physiol. 547, 649-663 CrossRef PubMed
85. Chen, G., Carroll, S., Racay, P., Dick, J., Pette, D., Traub, I., Vrbova, G., Eggli, P., Celio, M. and Schwaller, B. (2001) Deficiency in parvalbumin increases fatigue resistance in fast-twitch muscle and upregulates mitochondria. Am J Physiol. Cell Physiol. 281, C114-C122 PubMed
86. Gowans, G. J., Hawley, S. A., Ross, F. A. and Hardie, D. G. (2013) AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 18, 556-566 CrossRef PubMed
87. Hardie, D. G. (2014) AMP-activated protein kinase: A key regulator of energy balance with many roles in human disease. J. Intern. Med. 276, 543-559 CrossRef PubMed
88. O'Neill, H. M., Maarbjerg, S. J., Crane, J. D., Jeppesen, J., Jørgensen, S. B., Schertzer, J. D., Shyroka, O., Kiens, B., van Denderen, B. J., Tarnopolsky, M. A. et al. (2011) AMPK-activated protein kinase (AMPK) 12 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl. Acad. Sci. U. S. A. 108, 16092-16097 CrossRef PubMed
89. Bergeron, R., Ren, J. M., Cadman, K. S., Moore, I. K., Perret, P., Pypaert, M., Young, L. H., Semenkovich, C. F. and Shulman, G. I. (2001) Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. Endocrinol. Metab. 281, E1340-E1346 PubMed
90. Jäger, S., Handschin, C., St-Pierre, J. and Spiegelman, B. M. (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. U. S. A. 104, 12017-12022 CrossRef PubMed
91. Winder, W. W., Holmes, B. F., Rubink, D. S., Jensen, E. B., Chen, M. and Holloszy, J. O. (2000) Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88, 2219-2226 PubMed
92. Irrcher, I., Ljubicic, V., Kirwan, A. F. and Hood, D. A. (2008) AMP-activated protein kinase-regulated activation of the PGC-1alpha promoter in skeletal muscle cells. PLoS One 3, e3614 CrossRef PubMed
93. Garcia-Roves, P. M., Osler, M. E., Holmström, M. H. and Zierath, J. R. (2008) Gain-of-function R225Q mutation in AMP-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J. Biol. Chem. 283, 35724-35734 CrossRef PubMed
94. Irrcher, I., Ljubicic, V. and Hood, D. A. (2009) Interactions between ROS and AMP kinase activity in the regulation of PGC-1 transcription in skeletal muscle cells. Am. J. Physiol. Cell Physiol. 296, C116-C123 CrossRef PubMed
95. Hoffman, N. J., Parker, B. L., Chaudhuri, R., Fisher-Wellman, K. H., Kleinert, M., Humphrey, S. J., Yang, P., Holliday, M., Trefely, S., Fazakerley, D. J. et al. (2015) Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab. 22, 922-935 CrossRef PubMed
96. Rohas, L. M., St-Pierre, J., Uldry, M., Jäger, S., Handschin, C. and Spiegelman, B. M. (2007) A fundamental system of cellular energy homeostasis regulated by PGC-1alpha. Proc. Natl. Acad. Sci. U. S. A. 104, 7933-7938 CrossRef PubMed
97. Fan, M., Rhee, J., St-Pierre, J., Handschin, C., Puigserver, P., Lin, J., Jaeger, S., Erdjument-Bromage, H., Tempst, P. and Spiegelman, B. M. (2004) Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1: Modulation by p38 MAPK. Genes Dev. 18, 278-289 CrossRef PubMed
98. Pogozelski, A. R., Geng, T., Li, P., Yin, X., Lira, V. A., Zhang, M., Chi, J. T. and Yan, Z. (2009) p38 mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice. PLoS One 4, e7934 CrossRef PubMed
99. Yan, Z., Li, P. and Akimoto, T. (2007) Transcriptional control of the Pgc-1alpha gene in skeletal muscle in vivo. Exerc. Sport Sci. Rev. 35, 97-101 CrossRef PubMed
100. Kirkwood, S. P., Packer, L. and Brooks, G. A. (1987) Effects of endurance training on a mitochondrial reticulum in limb skeletal muscle. Arch. Biochem. Biophys. 255, 80-88 CrossRef PubMed
101. Kayar, S. R. and Banchero, N. (1987) Volume density and distribution of mitochondria in myocardial growth and hypertrophy. Respir. Physiol. 70, 275-286 CrossRef PubMed
102. Ogata, T. and Yamasaki, Y. (1997) Ultra-high-resolution scanning electron micrscopy of mitochondria and sarcoplasmic reticulum arrangement in human red, white and intermediate muscle fibers. Anat. Rec. 248, 1997 CrossRef
103. Ferreira, R., Vitorino, R., Alves, R. M. P., Appell, H. J., Powers, S. K., Duarte, J. A. and Amado, F. (2010) Subsarcolemmal and intermyofibrillar mitochondria proteome differences disclose functional specializations in skeletal muscle. Proteomics 10, 3142-3154
104. Takahashi, M. and Hood, D. A. (1996) Protein import into subsarcolemmal and intermyofibrillar muscle mitochondria: differential import regulation in distinct subcellular regions. J. Biol. Chem. 271, 27285-27291 CrossRef PubMed
105. Picard, M., Gentil, B. J., McManus, M. J., White, K., St. Louis, K., Gartside, S. E., Wallace, D. C. and Turnbull, D. M. (2013) Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle. J. Appl. Physiol. 115, 1562-1571 CrossRef PubMed
106. Picard, M., Shirihai, O. S., Gentil, B. J. and Burelle, Y. (2013) Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R393-R406 CrossRef
107. Losón, O. C., Song, Z., Chen, H. and Chan, D. C. (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol. Biol. Cell 24, 659-667 CrossRef PubMed
108. Song, Z., Ghochani, M., Mccaffery, J. M., Frey, T. G. and Chan, D. C. (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol. Biol. Cell 20, 3525-3532 CrossRef PubMed
109. Cartoni, R., Leger, B., Hock, M. B., Praz, M., Crettenand, A., Pich, S., Ziltener, J. L., Luthi, F., Olivier, D., Zorzano, A. et al. (2005) Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exercise. J. Physiol. 567, 349-358 CrossRef PubMed
110. Martin, O. J., Lai, L., Soundarapandian, M. M., Leone, T. C., Zorzano, A., Keller, M. P., Attie, A. D., Muoio, D. M. and Kelly, D. P. (2014) A role for peroxisome proliferator-activated receptor coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth. Circ. Res. 114, 626-636 CrossRef PubMed
111. Romanello, V., Guadagnin, E., Gomes, L., Roder, I., Sandri, C., Petersen, Y., Milan, G., Masiero, E., Del Piccolo, P., Foretz, M. et al. (2010) Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 29, 1774-1785 CrossRef PubMed
112. Varanita, T., Soriano, M. E., Romanello, V., Zaglia, T., Quintana-Cabrera, R., Semenzato, M., Menabò, R., Costa, V., Civiletto, G., Pesce, P. et al. (2015) The Opa1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab. 21, 834-844 CrossRef PubMed
113. Mishra, P., Varuzhanyan, G., Pham, A. H. and Chan, D. C. (2015) Mitochondrial dynamics is a distinguishing feature of skeletal muscle fiber types and regulates organellar compartmentalization. Cell Metab. 22, 1033-1044 CrossRef PubMed
114. Iqbal, S., Ostojic, O., Singh, K., Joseph, A. M. and Hood, D. A. (2013) Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse. Muscle Nerve 48, 963-970 CrossRef PubMed
115. Toyama, E. Q., Herzig, S., Courchet, J., Lewis Jr, T. L., Losón, O. C., Hellberg, K., Young, N. P., Chen, H., Polleux, F., Chan, D. C. and Shaw, R. J. (2016) AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275-281 CrossRef PubMed
116. Calvo, S. E., Clauser, K. R. and Mootha, V. K. (2016) MitoCarta2. 0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 44, D1251-D1257 CrossRef PubMed
117. MacKenzie, J. A. and Payne, R. M. (2007) Mitochondrial protein import and human health and disease. Biochim. Biophys. Acta 1772, 509-523 CrossRef PubMed
118. Maccecchini, M. L., Rudin, Y., Blobel, G. and Schatz, G. (1979) Import of proteins into mitochondria: precursor forms of the extramitochondrially made F1-ATPase subunits in yeast. Proc. Natl. Acad. Sci. U. S. A. 76, 343-347 CrossRef PubMed
119. Maccecchini, M. L., Rudin, Y. and Schatz, G. (1979) Transport of proteins across the mitochondrial outer membrane. A precursor form of the cytoplasmically made intermembrane enzyme cytochrome c peroxidase. J. Biol. Chem. 254, 7468-7471 PubMed
120. Hallermayer, G., Zimmerman, R. and Neupert, W. (1977) Transport of cytoplasmically synthesized proteins into the mitochondria in a cell free system from Neurospora crassa. Eur. J. Biochem. 81, 533-544 CrossRef PubMed
121. Omura, T. (1998) Mitochondria-targeting sequence, a multi-role sorting sequence recognized at all steps of protein import into mitochondria. J. Biochem. 123, 1010-1016 CrossRef PubMed
122. Mihara, K. and Omura, T. (1996) Cytoplasmic chaperones in precursor targeting to mitochondria: the role of MSF and hsp 70. Trends Cell Biol 6, 104-108 CrossRef PubMed
123. Yamano, K., Yatsukawa, Y.-I., Esaki, M., Hobbs, A. E., Jensen, R. E. and Endo, T. (2008) Tom20 and Tom22 share the common signal recognition pathway in mitochondrial protein import. J. Biol. Chem. 283, 3799-3807 CrossRef PubMed
124. van Wilpe, S., Ryan, M. T., Hill, K., Maarse, A. C., Meisinger, C., Brix, J., Dekker, P. J., Moczko, M., Wagner, R., Meijer, M. et al. (1999) Tom22 is a multifunctional organizer of the mitochondrial preprotein translocase. Nature 401, 485-489 CrossRef PubMed
125. Yamamoto, H., Fukui, K., Takahashi, H., Kitamura, S., Shiota, T., Terao, K., Uchida, M., Esaki, M., Nishikawa, S., Yoshihisa, T. et al. (2009) Roles of Tom70 in import of presequence-containing mitochondrial proteins. J. Biol. Chem. 284, 31635-31646 CrossRef PubMed
126. Bauer, M. F., Sirrenberg, C., Neupert, W. and Brunner, M. (1996) Role of Tim23 as voltage sensor and presequence receptor in protein import into mitochondria. Cell 87, 33-41 CrossRef PubMed
127. Bauer, M. F., Hofmann, S., Neupert, W. and Brunner, M. (2000) Protein translocation into mitochondria: the role of TIM complexes. Trends Cell Biol. 10, 25-31 CrossRef PubMed
128. Schneider, H., Arretz, M., Wachter, E. and Neupert, W. (1990) Matrix processing peptidase of mitochondria. Structure-function relationships. J. Biol. Chem. 265, 9881-9887 PubMed
129. Wenz, L. S., Opalinski, L., Wiedemann, N. and Becker, T. (2015) Cooperation of protein machineries in mitochondrial protein sorting. Biochim. Biophys. Acta 1853, 1119-1129 CrossRef PubMed
130. Takahashi, M., Chesley, A., Freyssenet, D. and Hood, D. A. (1998) Contractile activity-induced adaptations in the mitochondrial protein import system. Am. J. Physiol. 274, C1380-C1387 PubMed
131. Gordon, J. W., Rungi, A. A., Inagaki, H. and Hood, D. A. (2001) Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle. J. Appl. Physiol. 90, 389-396 CrossRef PubMed
132. Joseph, A.-M., Ljubicic, V., Adhihetty, P. J. and Hood, D. A. (2010) Biogenesis of the mitochondrial Tom40 channel in skeletal muscle from aged animals and its adaptability to chronic contractile activity. Am. J. Physiol. Cell Physiol. 298, C1308-C1314 CrossRef PubMed
133. Singh, K. and Hood, D. A. (2011) Effect of denervation-induced muscle disuse on mitochondrial protein import. Am. J. Physiol. Cell Physiol. 300, C138-C145 CrossRef PubMed
134. Tryon, L. D., Crilly, M. J. and Hood, D. A. (2015) Effects of denervation on the regulation of mitochondrial transcription factor A expression in skeletal muscle. Am. J. Physiol. Cell Physiol. 309, C228-C238 CrossRef PubMed
135. Zhang, Y., Iqbal, S., O'Leary, M. F. N., Menzies, K. J., Saleem, A., Ding, S. and Hood, D. A. (2013) Altered mitochondrial morphology and defective protein import reveal novel roles for Bax and/or Bak in skeletal muscle. Am. J. Physiol. Cell Physiol. 305, C502-C511 CrossRef PubMed
136. Hood, D. A., Simoneau, J. A., Kelly, A. M. and Pette, D. (1992) Effect of thyroid status on the expression of metabolic enzymes during chronic stimulation. Am. J. Physiol. 263, C788-C793 PubMed
137. Craig, E. E., Chesley, A. and Hood, D. A. (1998) Thyroid hormone modifies mitochondrial phenotype by increasing protein import without altering degradation. Am. J. Physiol. 275, C1508-C1515 PubMed
138. Yakubovskaya, E., Guja, K. E., Eng, E. T., Choi, W. S., Mejia, E., Beglov, D., Lukin, M., Kozakov, D. and Garcia-Diaz, M. (2014) Organization of the human mitochondrial transcription initiation complex. Nucleic Acids Res. 42, 4100-4112 CrossRef PubMed
139. Kukat, C., Wurm, C. A., Spåhr, H., Falkenberg, M. and Larsson, N. G. (2011) Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc. Natl. Acad. Sci. U. S. A. 108, 13534-13539 CrossRef PubMed
140. Bogenhagen, D. F. (2012) Mitochondrial DNA nucleoid structure. Biochim. Biophys. Acta 1819, 914-920 CrossRef PubMed
141. Bogenhagen, D. F., Rousseau, D. and Burke, S. (2008) The layered structure of human mitochondrial DNA nucleoids. J. Biol. Chem. 283, 3665-3675 CrossRef PubMed
142. Shi, Y., Dierckx, A., Wanrooij, P. H., Wanrooij, S., Larsson, N. G., Wilhelmsson, L. M., Falkenberg, M. and Gustafsson, C. M. (2012) Mammalian transcription factor A is a core component of the mitochondrial transcription machinery. Proc. Natl. Acad. Sci. U. S. A. 109, 16510-16515 CrossRef PubMed
143. Ekstrand, M. I., Falkenberg, M., Rantanen, A., Park, C. B., Gaspari, M., Hultenby, K., Rustin, P., Gustafsson, C. M. and Larsson, N. G. (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum. Mol. Genet. 13, 935-944 CrossRef PubMed
144. Kaufman, B. A., Durisic, N., Mativetsky, J. M., Costantino, S., Hancock, M. A., Grutter, P. and Shoubridge, E. A. (2007) The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. Mol. Biol. Cell 18, 3225-3236 CrossRef PubMed
145. Ngo, H. B., Kaiser, J. T. and Chan, D. C. (2011) The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat. Struct. Mol. Biol. 18, 1290-1206 CrossRef PubMed
146. Ngo, H. B., Lovely, G. A., Phillips, R. and Chan, D. C. (2014) Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nat. Commun. 5, 3077 CrossRef PubMed
147. Rubio-Cosials, A., Sidow, J. F., Jiménez-Menéndez, N., Fernández-Millán, P., Montoya, J., Jacobs, H. T., Coll, M., Bernadó, P. and Solà, M. (2011) Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter. Nat. Struct. Mol. Biol. 18, 1281-1289 CrossRef PubMed
148. Mcculloch, V. and Shadel, G. S. (2003) Human mitochondrial transcription factor B1 interacts with the C-terminal activation region of h-mtTFA and stimulates transcription independently of its RNA methyltransferase activity. Mol. Cell. Biol. 23, 5816-5824 CrossRef PubMed
149. Larsson, N. G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandowski, M., Barsh, G. S. and Clayton, D. A. (1998) Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature 18, 231-236 PubMed
150. Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Brüning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S. et al. (1999) Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat. Genet. 21, 133-137 CrossRef PubMed
151. Wredenberg, A., Wibom, R., Wilhelmsson, H., Graff, C., Wiener, H. H., Burden, S. J., Oldfors, A., Westerblad, H. and Larsson, N. G. (2002) Increased mitochondrial mass in mitochondrial myopathy mice. Proc. Natl. Acad. Sci. U. S. A. 99, 15066-15071 CrossRef PubMed
152. Silva, J. P., Graff, C., Magnuson, M. A., Berggren, P. O. and Larsson, N. G. (2000) Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat. Genet. 26, 336-340 CrossRef PubMed
153. Li, H., Wang, J., Wilhelmsson, H., Hansson, A., Thoren, P., Duffy, J., Rustin, P. and Larsson, N. G. (2000) Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy. Proc. Natl. Acad. Sci. U. S. A. 97, 3467-3472 CrossRef PubMed
154. Aydin, J., Andersson, D. C., Hänninen, S. L., Wredenberg, A., Tavi, P., Park, C. B., Nils-Göran, L., Bruton, J. D. and Westerblad, H. (2009) Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy. Hum. Mol. Genet. 18, 278-288 CrossRef PubMed
155. Lu, B., Lee, J., Nie, X., Li, M., Morozov, Y. I., Venkatesh, S., Bogenhagen, D. F., Temiakov, D. and Suzuki, C. K. (2013) Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol. Cell 49, 121-132 CrossRef PubMed
156. Wang, K. Z. Q., Zhu, J., Dagda, R. K., Uechi, G., Cherra, S. J., Gusdon, A. M., Balasubramani, M. and Chu, C. T. (2014) ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: implications for Parkinson's disease. Mitochondrion 17, 132-140 CrossRef PubMed
157. Collu-Marchese, M., Shuen, M., Pauly, M., Saleem, A. and Hood, D. A. (2015) The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation. Biosci. Rep. 35, e00221 PubMed
158. Perry, C. G., Lally, J., Holloway, G. P., Heigenhauser, G. J., Bonen, A. and Spriet, L. L. (2010) Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle. J. Physiol. 588, 4795-4810 CrossRef PubMed
159. Pilegaard, H., Saltin, B. and Neufer, P. D. (2003) Exercise induces transient transcriptional activation of the PGC-1 gene in human skeletal muscle. J. Physiol. 546, 851-858 CrossRef PubMed
160. Saleem, A. and Hood, D. A. (2013) Acute exercise induces tumour suppressor protein p53 translocation to the mitochondria and promotes a p53-Tfam-mitochondrial DNA complex in skeletal muscle. J. Physiol. 591, 3625-3636 CrossRef PubMed
161. Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C. and Spiegelman, B. M. (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115-124 CrossRef PubMed
162. Lai, R. Y. J., Ljubicic, V., D'souza, D. and Hood, D. A. (2010) Effect of chronic contractile activity on mRNA stability in skeletal muscle. Am. J. Physiol. Cell Physiol. 299, C155-C163 CrossRef PubMed
163. Pastore, S. and Hood, D. A. (2013) Endurance training ameliorates the metabolic and performance characteristics of circadian Clock mutant mice. J. Appl. Physiol. 114, 1076-1084 CrossRef PubMed
164. Bengtsson, J., Gustafsson, T., Widegren, U., Jansson, E. and Sundberg, C. J. (2001) Mitochondrial transcription factor A and respiratory complex IV increase in response to exercise training in humans. Pflugers Arch. 443, 61-66 CrossRef PubMed
165. Norrbom, J., Wallman, S. E., Gustafsson, T., Rundqvist, H., Jansson, E. and Sundberg, C. J. (2010) Training response of mitochondrial transcription factors in human skeletal muscle. Acta Physiol. (Oxf). 198, 71-79 CrossRef PubMed
166. Lane, D. P. (1992) Cancer. p53, guardian of the genome. Nature 358, 15-16 CrossRef PubMed
167. Levine, A. J., Hu, W. and Feng, Z. (2006) The P53 pathway: what questions remain to be explored Cell Death Differ. 13, 1027-1036 CrossRef PubMed
168. Maiuri, M. C., Tasdemir, E., Criollo, A., Morselli, E., Vicencio, J. M., Carnuccio, R. and Kroemer, G. (2009) Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ. 16, 87-93 CrossRef PubMed
169. Yu, J. and Zhang, L. (2005) The transcriptional targets of p53 in apoptosis control. Biochem. Biophys. Res. Commun. 331, 851-858 CrossRef PubMed
170. Bartlett, J. D., Close, G. L., Drust, B. and Morton, J. P. (2014) The emerging role of p53 in exercise metabolism. Sport. Med. 44, 303-309 CrossRef
171. Saleem, A., Carter, H. N., Iqbal, S. and Hood, D. A. (2011) Role of p53 within the regulatory network controlling muscle mitochondrial biogenesis. Exerc. Sport Sci. Rev. 39, 199-205 PubMed
172. Park, J., Zhuang, J., Li, J. and Hwang, P. M. (2016) p53 as guardian of the mitochondrial genome. FEBS Lett. 1-11
173. Zhou, S., Kachhap, S. and Singh, K. K. (2003) Mitochondrial impairment in p53-deficient human cancer cells. Mutagenesis 18, 287-292 CrossRef PubMed
174. Saleem, A., Carter, H. N. and Hood, D. A. (2014) p53 is necessary for the adaptive changes in the cellular milieu subsequent to an acute bout of endurance exercise. Am. J. Physiol. Cell Physiol. 306, C241-C249 CrossRef PubMed
175. Saleem, A., Iqbal, S., Zhang, Y. and Hood, D. A. (2015) Effect of p53 on mitochondrial morphology, import and assembly in skeletal muscle. Am. J. Physiol. Cell Physiol. 308, C319-C329 CrossRef PubMed
176. Matoba, S., Kang, J.-G., Patino, W. D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P. J., Bunz, F. and Hwang, P. M. (2006) p53 regulates mitochondrial metabolism. Science 312, 1650-1653 CrossRef PubMed
177. Donahue, R. J., Razmara, M., Hoek, J. B. and Knudsen, T. B. (2001) Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function. FASEB J. 15, 635-644 CrossRef PubMed
178. Heyne, K., Mannebach, S., Wuertz, E., Knaup, K. X., Mahyar-Roemer, M. and Roemer, K. (2004) Identification of a putative p53 binding sequence within the human mitochondrial genome. FEBS Lett. 578, 198-202 CrossRef PubMed
179. Riley, T., Sontag, E., Chen, P. and Levine, A. (2008) Transcriptional control of human p53 regulated genes. Nat. Rev. Mol. Cell Biol. 9, 402-412 CrossRef PubMed
180. Green, D. R. and Kroemer, G. (2009) Cytoplasmic functions of the tumour suppressor p53. Nature 458, 1127-1130 CrossRef PubMed
181. Park, J.-Y., Wang, P.-Y., Matsumoto, T., Sung, H. J., Ma, W., Choi, J. W., Anderson, S. A., Leary, S. C., Balaban, R. S., Kang, J.-G. and Hwang, P. M. (2009) p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content. Circ. Res. 105, 705-712 CrossRef PubMed
182. Yoshida, Y., Izumi, H., Torigoe, T., Ishiguchi, H., Itoh, H., Kang, D. and Kohno, K. (2003) p53 physically interacts with mitochondrial transcription factor A and differentially regulates binding to damaged DNA. Cancer Res. 63, 3729-3734 PubMed
183. Lee, J., Giordano, S. and Zhang, J. (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem. J. 441, 523-540 CrossRef PubMed
184. Granata, C., Oliveira, R. S., Little, J. P., Renner, K. and Bishop, D. J. (2016) Training intensity modulates changes in PGC-1 and p53 protein content and mitochondrial respiration, but not markers of mitochondrial content in human skeletal muscle. FASEB J. 30, 959-970 CrossRef PubMed
185. She, Q.-B., Bode, A. M., Ma, W.-Y., Chen, N.-Y. and Dong, Z. (2001) Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res. 61, 1604-1610 PubMed
186. Jones, R. G., Plas, D. R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., Birnbaum, M. J. and Thompson, C. B. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283-293 CrossRef PubMed
187. Winder, W. W. and Hardie, D. G. (1996) Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am. J. Physiol. Endocrinol. Metab. 270, E299-E304 PubMed
188. Bartlett, J. D., Hwa Joo, C., Jeong, T. S., Louhelainen, J., Cochran, A. J., Gibala, M. J., Gregson, W., Close, G. L., Drust, B. and Morton, J. P. (2012) Matched work high-intensity interval and continuous running induce similar increases in PGC-1 mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle. J. Appl. Physiol. 112, 1135-1143 CrossRef PubMed
189. Bartlett, J. D., Louhelainen, J., Iqbal, Z., Cochran, A. J., Gibala, M. J., Gregson, W., Close, G. L., Drust, B. and Morton, J. P. (2013) Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: implications for mitochondrial biogenesis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R450-R458 CrossRef PubMed
190. Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S. I., Frye, R. A., Pandita, T. K., Guarente, L. and Weinberg, R. A. (2001) hSIR2 (SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149-159 CrossRef PubMed
191. Philp, A., Chen, A., Lan, D., Meyer, G. A., Murphy, A. N., Knapp, A. E., Olfert, I. M., McCurdy, C. E., Marcotte, G. R., Hogan, M. C. et al. (2011) Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) deacetylation following endurance exercise. J. Biol. Chem. 286, 30561-30570 CrossRef PubMed
192. Kim, J., Kundu, M., Viollet, B. and Guan, K. L. (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132-141 CrossRef PubMed
193. Tassa, A., Roux, M. P., Attaix, D. and Bechet, D. M. (2003) Class III phosphoinositide 3-kinase-Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem. J. 376, 577-586 CrossRef PubMed
194. Nakatogawa, H. (2013) Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy. Essays Biochem. 55, 39-50 CrossRef PubMed
195. Parzych, K. R. and Klionsky, D. J. (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid. Redox Signal. 20, 460-473 CrossRef PubMed
196. Feng, Y., He, D., Yao, Z. and Klionsky, D. J. (2014) The machinery of macroautophagy. Cell Res. 24, 24-41 CrossRef PubMed
197. Jin, S. M., Lazarou, M., Wang, C., Kane, L. A., Narendra, D. P. and Youle, R. J. (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933-942 CrossRef PubMed
198. Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., Sou, Y.-S., Saiki, S., Kawajiri, S., Sato, F. et al. (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211-221 CrossRef PubMed
199. Sun, Y., Vashisht, A. A., Tchieu, J., Wohlschlegel, J. A. and Dreier, L. (2012) Voltage-dependent anion channels (VDACs) recruit parkin to defective mitochondria to promote mitochondrial autophagy. J. Biol. Chem. 287, 40652-40660 CrossRef PubMed
200. Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J. and Springer, W. (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119-131 CrossRef PubMed
201. Tanaka, A., Cleland, M. M., Xu, S., Narendra, D. P., Suen, D., Karbowski, M. and Youle, R. J. (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367-1380 CrossRef PubMed
202. Gegg, M. E., Cooper, J. M., Chau, K. Y., Rojo, M., Schapira, A. H. V. and Taanman, J. W. (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 19, 4861-4870 CrossRef PubMed
203. Chen, Y. and Dorn, G. W. (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471-475 CrossRef PubMed
204. Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G. and Johansen, T. (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131-24145 CrossRef PubMed
205. Ladror, U. S., Snyder, S. W., Wang, G. T., Holzman, T. F. and Krafft, G. A. (1994) Cleavage at the amino and carboxyl termini of Alzheimer's amyloid-beta by cathepsin D. J. Biol. Chem. 269, 18422-18428 PubMed
206. Lira, V. A., Okutsu, M., Zhang, M., Greene, N. P., Laker, R. C., Breen, D. S., Hoehn, K. L. and Yan, Z. (2013) Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J. 27, 4184-4193 CrossRef PubMed
207. Schott, L. H. and Terjung, R. L. (1979) The influence of exercise on muscle lysosomal enzymes. Eur. J. Appl. Physiol. 42, 175-182 CrossRef
208. Salminen, A., Hongisto, K. and Vihko, V. (1984) Lysosomal changes related to exercise injuries and training-induced protection in mouse skeletal muscle. Acta Physiol. Scand. 120, 15-19 CrossRef PubMed
209. He, C., Bassik, M. C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q. et al. (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511-515 CrossRef PubMed
210. Jamart, C., Benoit, N., Raymackers, J. M., Kim, H. J., Kim, C. K. and Francaux, M. (2012) Autophagy-related and autophagy-regulatory genes are induced in human muscle after ultraendurance exercise. Eur. J. Appl. Physiol. 112, 3173-3177 CrossRef PubMed
211. Jamart, C., Francaux, M., Millet, G. Y., Deldicque, L., Frère, D. and Féasson, L. (2012) Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running. J. Appl. Physiol. 112, 1529-1537 CrossRef PubMed
212. Grumati, P., Coletto, L., Schiavinato, A., Castagnaro, S., Bertaggia, E., Sandri, M. and Bonaldo, P. (2014) Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles. Autophagy 7, 1415-1423 CrossRef
213. Pagano, A. F., Py, G., Bernardi, H., Candau, R. B. and Sanchez, A. M. (2014) Autophagy and protein turnover signaling in slow-twitch muscle during exercise. Med. Sci. Sports Exerc. 46, 1314-1325 CrossRef PubMed
214. Møller, A. B., Vendelbo, M. H., Christensen, B., Clasen, B. F., Bak, A. M., Jørgensen, J. O., Møller, N. and Jessen, N. (2015) Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle. J. Appl. Physiol. 118, 971-979 CrossRef PubMed
215. Schwalm, C., Jamart, C., Benoit, N., Naslain, D., Prémont, C., Prevet, J., Van Thienen, R., Deldicque, L. and Francaux, M. (2015) Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. FASEB J. 29, 3515-3526 CrossRef PubMed
216. Fritzen, A. M., Madsen, A. B., Kleinert, M., Treebak, J. T., Lundsgaard, A.-M., Jensen, T. E., Richter, E. A., Wojtaszewski, J., Kiens, B. and Frøsig, C. (2016) Regulation of autophagy in human skeletal muscle-effects of exercise, exercise training and insulin stimulation. J. Physiol. 594, 745-761 CrossRef PubMed
217. LoVerso, F., Carnio, S., Vainshtein, A. and Sandri, M. (2014) Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity. Autophagy 10, 1883-1894 CrossRef PubMed
218. Halling, J. F., Ringholm, S., Nielsen, M. M., Overby, P. and Pilegaard, H. (2016) PGC-1 promotes exercise-induced autophagy in mouse skeletal muscle. Physiol. Rep. 4, e12698 CrossRef PubMed
219. Settembre, C., Di Malta, C., Polito, V. A., Garcia Arencibia, M., Vetrini, F., Erdin, S., Erdin, S. U., Huynh, T., Medina, D., Colella, P. et al. (2011) TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433 CrossRef PubMed
220. Sardiello, M., Palmieri, M., di Ronza, A., Medina, D. L., Valenza, M., Gennarino, V. A., Di Malta, C., Donaudy, F., Embrione, V., Polishchuk, R. S. et al. (2009) A gene network regulating lysosomal biogenesis and function. Science 325, 473-477 PubMed
221. Settembre, C., De Cegli, R., Mansueto, G., Saha, P. K., Vetrini, F., Visvikis, O., Huynh, T., Carissimo, A., Palmer, D., Jürgen Klisch, T. et al. (2013) TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647-658 CrossRef PubMed
222. Settembre, C., Zoncu, R., Medina, D. L., Vetrini, F., Erdin, S., Erdin, S., Huynh, T., Ferron, M., Karsenty, G., Vellard, M. C. et al. (2012) A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095-1108 CrossRef PubMed
223. Martina, J. A., Chen, Y., Gucek, M. and Puertollano, R. (2012) MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903-914 CrossRef PubMed
224. Unuma, K., Aki, T., Funakoshi, T., Yoshida, K. and Uemura, K. (2013) Cobalt protoporphyrin accelerates TFEB activation and lysosome reformation during LPS-induced septic insults in the rat heart. PLoS One 8, e56526 CrossRef PubMed
225. Medina, D. L., Di Paola, S., Peluso, I., Armani, A., De Stefani, D., Venditti, R., Montefusco, S., Scotto-Rosato, A., Prezioso, C., Forrester, A. et al. (2015) Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17, 288-299 CrossRef PubMed
226. Vainshtein, A., Desjardins, E. M. A., Armani, A., Sandri, M. and Hood, D. A. (2015) PGC-1 modulates denervation-induced mitophagy in skeletal muscle. Skelet. Muscle 5, 1-17 CrossRef PubMed
227. Tsunemi, T., Ashe, T. D., Morrison, B. E., Soriano, K. R., Au, J., Roque, R. A. V., Lazarowski, E. R., Damian, V. A., Masliah, E. and La Spada, A. R. (2012) PGC-1 rescues Huntington's diseases proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4, 142ra97 CrossRef PubMed
228. Morey-Holton, E. R. and Globus, R. K. (1998) Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight. Bone 22, 83S-88S CrossRef PubMed
229. Morey-Holton, E. R. and Globus, R. K. (2002) Hindlimb unloading rodent model: technical aspects. J. Appl. Physiol. 92, 1367-1377 CrossRef PubMed
230. Adhihetty, P. J., O'Leary, M. F. N., Chabi, B., Wicks, K. L. and Hood, D. A. (2007) Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle. J. Appl. Physiol. 3, 1143-1151 PubMed
231. Gauthier, G. F. and Dunn, R. A. (1973) Ultrastructural and cytochemical features of mammalian skeletal muscle fibers following denervation. J. Cell. Sci. 12, 525-547 PubMed
232. Liu, J., Peng, Y., Feng, Z., Shi, W., Qu, L., Li, Y., Liu, J. and Long, J. (2014) Reloading functionally ameliorates disuse-induced muscle atrophy by reversing mitochondrial dysfunction, and similar benefits are gained by administering a combination of mitochondrial nutrients. Free Radic. Biol. Med. 69, 116-128 CrossRef PubMed
233. Tomanek, R. J. and Lund, D. D. (1973) Degeneration of different types of skeletal muscle fibres. I. Denervation. J. Anat. 116, 395-407 PubMed
234. Pellegrino, C. and Franzini, C. (1963) An electron microscope study of denervation atrophy in red and white skeletal muscle fibers. J. Cell Biol. 17, 327-349 CrossRef PubMed
235. Lu, D. X., Huang, S. K. and Carlson, B. M. (1997) Electron microscopic study of long-term denervated rat skeletal muscle. Anat. Rec. 248, 355-365 CrossRef PubMed
236. Wagatsuma, A., Kotake, N., Mabuchi, K. and Yamada, S. (2011) Expression of nuclear-encoded genes involved in mitochondrial biogenesis and dynamics in experimentally denervated muscle. J. Physiol. Biochem. 67, 359-370 CrossRef PubMed
237. Raffaello, A., Laveder, P., Romualdi, C., Bean, C., Toniolo, L., Germinario, E., Megighian, A., Danieli-Betto, D., Reggiani, C. and Lanfranchi, G. (2006) Denervation in murine fast-twitch muscle: short-term physiological changes and temporal expression profiling. Physiol. Genomics 25, 60-74 CrossRef PubMed
238. Brault, J. J., Jespersen, J. G. and Goldberg, A. L. (2010) Peroxisome proliferator-activated receptor coactivator 1 or 1B overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J. Biol. Chem. 285, 19460-19471 CrossRef PubMed
239. Muller, F. L., Song, W., Jang, Y. C., Liu, Y., Sabia, M., Richardson, A. and Van Remmen, H. (2007) Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1159-R1168 CrossRef PubMed
240. Sacheck, J. M., Hyatt, J. P., Raffaello, A., Jagoe, R. T., Roy, R. R., Edgerton, V. R., Lecker, S. H. and Goldberg, A. L. (2007) Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J. 21, 140-155 CrossRef PubMed
241. Sandri, M., Lin, J., Handschin, C., Yang, W., Arany, Z. P., Lecker, S. H., Goldberg, A. L. and Spiegelman, B. M. (2006) PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl. Acad. Sci. U. S. A. 103, 16260-16265 CrossRef PubMed
242. Hindi, S. M., Mishra, V., Bhatnagar, S., Tajrishi, M. M., Ogura, Y., Yan, Z., Burkly, L. C., Zheng, T. S. and Kumar, A. (2014) Regulatory circuitry of TWEAK-Fn14 system and PGC-1 in skeletal muscle atrophy program. FASEB J. 28, 1398-1411 CrossRef PubMed
243. Kang, C. and Ji, L. L. (2013) Muscle immobilization and remobilization downregulates PGC-1 signaling and the mitochondrial biogenesis pathway. J. Appl. Physiol. 115, 1618-1625 CrossRef PubMed
244. Cannavino, J., Brocca, L., Sandri, M., Grassi, B., Bottinelli, R. and Pellegrino, M. A. (2015) The role of alterations in mitochondrial dynamics and PGC-1 over-expression in fast muscle atrophy following hindlimb unloading. J. Physiol. 593, 1981-1995 CrossRef PubMed
245. Cannavino, J., Brocca, L., Sandri, M., Bottinelli, R. and Pellegrino, M. A. (2014) PGC-1 over-expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice. J. Physiol. 592, 4575-4589 CrossRef PubMed
246. Kang, C., Goodman, C. A., Hornberger, T. A. and Ji, L. L. (2015) PGC-1 overexpression by in vivo transfection attenuates mitochondrial deterioration of skeletal muscle caused by immobilization. FASEB J. 29, 4092-4106 CrossRef PubMed
247. Kang, C. and Ji, L. L. (2016) PGC-1 overexpression via local transfection attenuates mitophagy pathway in muscle disuse atrophy. Free Radic. Biol. Med. 93, 32-40 CrossRef PubMed
248. Touvier, T., De Palma, C., Rigamonti, E., Scagliola, A., Incerti, E., Mazelin, L., Thomas, J.-L., D'Antonio, M., Politi, L., Schaeffer, L. et al. (2015) Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation. Cell Death Dis. 6, e1663 CrossRef PubMed
249. O'Leary, M. F. N. and Hood, D. A. (2009) Denervation-induced oxidative stress and autophagy signaling in muscle. Autophagy 5, 230-231 CrossRef PubMed
250. Johnson, M. L., Robinson, M. M. and Nair, K. S. (2013) Skeletal muscle aging and the mitochondrion. Trends Endocrinol. Metab. 24, 247-256 CrossRef PubMed
251. Hepple, R. T. (2014) Mitochondrial involvement and impact in aging skeletal muscle. Front. Aging Neurosci. 6, 211 CrossRef PubMed
252. Thrush, A. B., Dent, R., McPherson, R. and Harper, M.-E. (2013) Implications of mitochondrial uncoupling in skeletal muscle in the development and treatment of obesity. FEBS J. 280, 5015-5029 CrossRef PubMed
253. Patti, M.-E. and Corvera, S. (2010) The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr. Rev. 31, 364-395 CrossRef PubMed
254. Huang, J. H. and Hood, D. A. (2009) Age-associated mitochondrial dysfunction in skeletal muscle: contributing factors and suggestions for long-term interventions. IUBMB Life 61, 201-214 CrossRef PubMed
255. Ljubicic, V., Joseph, A.-M., Saleem, A., Uguccioni, G., Collu-Marchese, M., Lai, R. Y. J., Nguyen, L. M.-D. and Hood, D. A. (2010) Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging. Biochim. Biophys. Acta 1800, 223-234 CrossRef PubMed
256. Conley, K. E., Marcinek, D. J. and Villarin, J. (2007) Mitochondrial dysfunction and age. Curr. Opin. Clin. Nutr. Metab. Care 10, 688-692 CrossRef PubMed
257. Ji, L. L. and Kang, C. (2015) Role of PGC-1 in sarcopenia: etiology and potential intervention-A mini-review. Gerontology 61, 139-148 CrossRef PubMed
258. Kruse, S. E., Karunadharma, P. P., Basisty, N., Johnson, R., Beyer, R. P., MacCoss, M. J., Rabinovitch, P. S. and Marcinek, D. J. (2016) Age modifies respiratory complex I and protein homeostasis in a muscle type-specific manner. Aging Cell 15, 89-99 CrossRef PubMed
259. McDonagh, B., Sakellariou, G. K., Smith, N. T., Brownridge, P. and Jackson, M. J. (2014) Differential cysteine labeling and global label-free proteomics reveals an altered metabolic state in skeletal muscle aging. J. Proteome Res. 13, 5008-5021 CrossRef PubMed
260. Welle, S., Bhatt, K., Shah, B., Needler, N., Delehanty, J. M. and Thornton, C. A. (2003) Reduced amount of mitochondrial DNA in aged human muscle. J. Appl. Physiol. 94, 1479-1484 CrossRef PubMed
261. Huang, J. H., Joseph, A. M., Ljubicic, V., Iqbal, S. and Hood, D. A. (2010) Effect of age on the processing and import of matrix-destined mitochondrial proteins in skeletal muscle. J. Gerontol. A Biol. Sci. Med. Sci. 65, 138-146 CrossRef PubMed
262. Ljubicic, V., Joseph, A. M., Adhihetty, P. J., Huang, J. H., Saleem, A., Uguccioni, G. and Hood, D. A. (2009) Molecular basis for an attenuated mitochondrial adaptive plasticity in aged skeletal muscle. Aging 1, 818-831 CrossRef PubMed
263. Crane, J. D., Devries, M. C., Safdar, A., Hamadeh, M. J. and Tarnopolsky, M. A. (2010) The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J. Gerontol. A Biol. Sci. Med. Sci. 65, 119-128 CrossRef PubMed
264. Conley, K. E., Jubrias, S. A. and Esselman, P. C. (2000) Oxidative capacity and ageing in human muscle. J. Physiol. 526, 203-210 CrossRef PubMed
265. Porter, C., Hurren, N. M., Cotter, M. V, Bhattarai, N., Reidy, P. T., Dillon, E. L., Durham, W. J., Tuvdendorj, D., Sheffield-Moore, M., Volpi, E. et al. (2015) Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 309, E224-E232 CrossRef PubMed
266. O'Leary, M. F., Vainshtein, A., Iqbal, S., Ostojic, O. and Hood, D. A. (2013) Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle. Am. J. Physiol. Cell Physiol. 304, C422-C430 CrossRef PubMed
267. Cortopassi, G. A. and Arnheim, N. (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 6927-6933 CrossRef PubMed
268. Cortopassi, G. A., Shibata, D., Soong, N. W. and Arnheim, N. (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc. Natl. Acad. Sci. U. S. A. 89, 7370-7374 CrossRef PubMed
269. Chabi, B., Ljubicic, V., Menzies, K. J., Huang, J. H., Saleem, A. and Hood, D. A. (2008) Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging Cell 7, 2-12 CrossRef PubMed
270. Wenz, T., Rossi, S. G., Rotundo, R. L., Spiegelman, B. M. and Moraes, C. T. (2009) Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc. Natl. Acad. Sci. U. S. A. 106, 20405-20410 CrossRef PubMed
271. Leick, L., Lyngby, S. S., Wojtaszewski, J. F. P. and Pilegaard, H. (2010) PGC-1alpha is required for training-induced prevention of age-associated decline in mitochondrial enzymes in mouse skeletal muscle. Exp. Gerontol. 45, 336-342 CrossRef PubMed
272. Vainshtein, A. and Hood, D. A. (2016) The regulation of autophagy during exercise in skeletal muscle. J. Appl. Physiol. 120, 664-673 CrossRef PubMed
273. Zampieri, S., Pietrangelo, L., Loefler, S., Fruhmann, H., Vogelauer, M., Burggraf, S., Pond, A., Grim-Stieger, M., Cvecka, J., Sedliak, M. et al. (2014) Lifelong physical exercise delays age-associated skeletal muscle decline. J. Gerontol. A Biol. Sci. Med. Sci. 70, 163-173 CrossRef PubMed
274. Trappe, S., Hayes, E., Galpin, A., Kaminsky, L., Jemiolo, B., Fink, W., Trappe, T., Jansson, A., Gustafsson, T. and Tesch, P. (2013) New records in aerobic power among octogenarian lifelong endurance athletes. J. Appl. Physiol. 114, 3-10 CrossRef PubMed
275. Joseph, A. M., Adhihetty, P. J., Buford, T. W., Wohlgemuth, S. E., Lees, H. A., Nguyen, L. M. D., Aranda, J. M., Sandesara, B. D., Pahor, M., Manini, T. M. et al. (2012) The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high-and low-functioning elderly individuals. Aging Cell 11, 801-809 CrossRef PubMed
276. Gouspillou, G., Sgarioto, N., Kapchinsky, S., Purves-Smith, F., Norris, B., Pion, C. H., Barbat-Artigas, S., Lemieux, F., Taivassalo, T., Morais, J. A. et al. (2014) Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 28, 1621-1633 CrossRef PubMed
277. Gram, M., Vigelsø, A., Yokota, T., Helge, J. W., Dela, F. and Hey-Mogensen, M. (2015) Skeletal muscle mitochondrial H2O2 emission increases with immobilization and decreases after aerobic training in young and older men. J. Physiol. 593, 4011-4027 CrossRef PubMed
278. Ghosh, S., Lertwattanarak, R., Lefort, N., Molina-Carrion, M., Joya-Galeana, J., Bowen, B. P., Garduno-Garcia J. de, J., Abdul-Ghani, M., Richardson, A., DeFronzo, R. A. et al. (2011) Reduction in reactive oxygen species production by mitochondria from elderly subjects with normal and impaired glucose tolerance. Diabetes 60, 2051-2060 CrossRef PubMed
279. Kent-Braun, J. A. and Ng, A. V. (2000) Skeletal muscle oxidative capacity in young and older women and men. J. Appl. Physiol. 89, 1072-1078 PubMed
280. Larsen, R. G., Callahan, D. M., Foulis, S. A. and Kent-Braun, J. A. (2012) Age-related changes in oxidative capacity differ between locomotory muscles and are associated with physical activity behavior. Appl. Physiol. Nutr. Metab. 37, 88-99 CrossRef PubMed
281. Irving, B. A., Lanza, I. R., Henderson, G. C., Rao, R. R., Spiegelman, B. M. and Nair, K. S. (2015) Combined training enhances skeletal muscle mitochondrial oxidative capacity independent of age. J. Clin. Endocrinol. Metab. 100, 1654-1663 CrossRef PubMed
282. Ljubicic, V. and Hood, D. A. (2009) Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscle. Aging Cell 8, 394-404 CrossRef PubMed
283. Walters, T. J., Sweeney, H. L. and Farrar, R. P. (1991) Influence of electrical stimulation on a fast-twitch muscle in aging rats. J. Appl. Physiol. 71, 1921-1928 PubMed
284. Handschin, C. (2016) Caloric restriction and exercise "mimetics": ready for prime time Pharmacol. Res. 103, 158-166 CrossRef PubMed
285. Craig, D. M., Ashcroft, S. P., Belew, M. Y., Stocks, B., Currell, K., Baar, K. and Philp, A. (2015) Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis. Front. Physiol. 6, 1-11 CrossRef PubMed
286. Sabina, R. L., Holmes, E. W. and Becker, M. A. (1984) The enzymatic synthesis of 5-amino-4-imidazolecarboxamide riboside triphosphate (ZTP). Science 223, 1193-1195 CrossRef PubMed
287. Corton, J. M., Gillespie, J. G., Hawley, S. A. and Hardie, D. G. (1995) 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells Eur. J. Biochem. 229, 558-565 CrossRef PubMed
288. O'Neill, H. M., Holloway, G. P. and Steinberg, G. R. (2013) AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: Implications for obesity. Mol. Cell. Endocrinol. 366, 135-151 CrossRef PubMed
289. Suwa, M., Nakano, H. and Kumagai, S. (2003) Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J. Appl. Physiol. 95, 960-968 CrossRef PubMed
290. Lira, V. A., Brown, D. L., Lira, A. K., Kavazis, A. N., Soltow, Q. A., Zeanah, E. H. and Criswell, D. S. (2010) Nitric oxide and AMPK cooperatively regulate PGC-1 in skeletal muscle cells. J. Physiol. 588, 3551-3566 CrossRef PubMed
291. Gurd, B. J., Yoshida, Y., Lally, J., Holloway, G. P. and Bonen, A. (2009) The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis. J. Physiol. 587, 1817-1828 CrossRef PubMed
292. Narkar, V. A., Downes, M., Yu, R. T., Embler, E., Wang, Y. X., Banayo, E., Mihaylova, M. M., Nelson, M. C., Zou, Y., Juguilon, H. et al. (2008) AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405-415 CrossRef PubMed
293. Jørgensen, S. B., Treebak, J. T., Viollet, B., Schjerling, P., Vaulont, S., Wojtaszewski, J. F. P. and Richter, E. A. (2007) Role of AMPKalpha2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle. Am. J. Physiol. Endocrinol. Metab. 292, E331-E339 PubMed
294. Dixon, R., Gourzis, J., McDermott, D., Fujitaki, J., Dewland, P. and Gruber, H. (1991) AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent. J. Clin. Pharmacol. 31, 342-347 CrossRef PubMed
295. Guigas, B., Sakamoto, K., Taleux, N., Reyna, S. M., Musi, N., Viollet, B. and Hue, L. (2009) Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB Life 61, 18-26 CrossRef PubMed
296. Sznaidman, M. L., Haffner, C. D., Maloney, P. R., Fivush, A., Chao, E., Goreham, D., Sierra, M. L., LeGrumelec, C., Xu, H. E., Montana, V. G. et al. (2003) Novel selective small molecule agonists for peroxisome proliferator-activated receptor (PPAR?)-synthesis and biological activity. Bioorg. Med. Chem. Lett. 13, 1517-1521 CrossRef PubMed
297. Neels, J. G. and Grimaldi, P. A. (2014) Physiological functions of peroxisome proliferator-activated receptor ?. Physiol. Rev. 94, 795-858 CrossRef PubMed
298. Schuler, M., Ali, F., Chambon, C., Duteil, D., Bornert, J. M., Tardivel, A., Desvergne, B., Wahli, W., Chambon, P. and Metzger, D. (2006) PGC1 expression is controlled in skeletal muscles by PPAR, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab. 4, 407-414 CrossRef PubMed
299. Luquet, S., Lopez-Soriano, J., Holst, D., Fredenrich, A., Melki, J., Rassoulzadegan, M. and Grimaldi, P. A. (2003) Peroxisome proliferator-activated receptor controls muscle development and oxidative capability. FASEB J. 17, 2299-2301 PubMed
300. Dimopoulos, N., Watson, M., Green, C. and Hundal, H. S. (2007) The PPARδ agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilisation or insulin sensitivity in rat L6 skeletal muscle cells. FEBS Lett. 581, 4743-4748 CrossRef PubMed
301. Tanaka, T., Yamamoto, J., Iwasaki, S., Asaba, H., Hamura, H., Ikeda, Y., Watanabe, M., Magoori, K., Ioka, R. X., Tachibana, K. et al. (2003) Activation of peroxisome proliferator-activated receptor induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl. Acad. Sci. U. S. A. 100, 15924-15929 CrossRef PubMed
302. Kleiner, S., Nguyen-Tran, V., Baré, O., Huang, X., Spiegelman, B. and Wu, Z. (2009) PPAR? agonism activates fatty acid oxidation via PGC-1 but does not increase mitochondrial gene expression and function. J. Biol. Chem. 284, 18624-18633 CrossRef PubMed
303. Dressel, U., Allen, T. L., Pippal, J. B., Rohde, P. R., Lau, P. and Muscat, G. E. O. (2003) The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol. Endocrinol. 17, 2477-2493 CrossRef PubMed
304. Krämer, D. K., Al-Khalili, L., Guigas, B., Leng, Y., Garcia-Roves, P. M. and Krook, A. (2007) Role of AMP kinase and PPAR? in the regulation of lipid and glucose metabolism in human skeletal muscle. J. Biol. Chem. 282, 19313-19320 CrossRef PubMed
305. Smoliga, J. M., Baur, J. A. and Hausenblas, H. A. (2011) Resveratrol and health-A comprehensive review of human clinical trials. Mol. Nutr. Food Res. 55, 1129-1141 CrossRef PubMed
306. Rodrigo, R., Miranda, A. and Vergara, L. (2011) Modulation of endogenous antioxidant system by wine polyphenols in human disease. Clin. Chim. Acta 412, 410-424 CrossRef PubMed
307. Kulkarni, S. S. and Canto, C. (2015) The molecular targets of resveratrol. Biochim. Biophys. Acta. 1852, 1114-1123 CrossRef PubMed
308. Price, N. L., Gomes, A. P., Ling, A. J. Y., Duarte, F. V., Martin-Montalvo, A., North, B. J., Agarwal, B., Ye, L., Ramadori, G., Teodoro, J. S. et al. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675-690 CrossRef PubMed
309. Higashida, K., Kim, S. H., Jung, S. R., Asaka, M., Holloszy, J. O. and Han, D. H. (2013) Effects of resveratrol and SIRT1 on PGC-1 activity and mitochondrial biogenesis: a reevaluation. PLoS Biol. 11, e1001603 CrossRef PubMed
310. Gerhart-Hines, Z., Rodgers, J. T., Bare, O., Lerin, C., Kim, S.-H., Mostoslavsky, R., Alt, F. W., Wu, Z. and Puigserver, P. (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 26, 1913-1923 CrossRef PubMed
311. Nemoto, S., Fergusson, M. M. and Finkel, T. (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1alpha. J. Biol. Chem. 280, 16456-16460 CrossRef PubMed
312. Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M. and Puigserver, P. (2005) Nutrient control of glucose homeostasis through a complex of PGC-1 and SIRT1. Nature 434, 113-118 CrossRef PubMed
313. Ljubicic, V., Burt, M., Lunde, J. A. and Jasmin, B. J. (2014) Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1a axis. Am. J. Physiol. Cell Physiol. 307, 66-82 CrossRef
314. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P. et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1. Cell 127, 1109-1122 CrossRef PubMed
315. Williams, C. B., Hughes, M. C., Edgett, B. A., Scribbans, T. D., Simpson, C. A., Perry, C. G. R. and Gurd, B. J. (2014) An examination of resveratrol's mechanisms of action in human tissue: Impact of a single dose in vivo and dose responses in skeletal muscle ex vivo. PLoS One 9, e102406 CrossRef PubMed
316. Scribbans, T. D., Ma, J. K., Edgett, B. A., Vorobej, K. A., Mitchell, A. S., Zelt, J. G. E., Simpson, C. A., Quadrilatero, J. and Gurd, B. J. (2014) Resveratrol supplementation does not augment performance adaptations or fibre-type-specific responses to high-intensity interval training in humans. Appl. Physiol. Nutr. Metab. 1313, 1-9 PubMed
317. Timmers, S., Konings, E., Bilet, L., Houtkooper, R. H., Van De Weijer, T., Goossens, G. H., Hoeks, J., Van Der Krieken, S., Ryu, D., Kersten, S. et al. (2011) Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612-622 CrossRef PubMed
318. Olesen, J., Gliemann, L., Biensø, R., Schmidt, J., Hellsten, Y. and Pilegaard, H. (2014) Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men. J. Physiol. 592, 1873-1886 CrossRef PubMed
319. Gliemann, L., Schmidt, J. F., Olesen, J., Biensø, R. S., Peronard, S. L., Grandjean, S. U., Mortensen, S. P., Nyberg, M., Bangsbo, J., Pilegaard, H. and Hellsten, Y. (2013) Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J. Physiol. 591, 5047-5059 CrossRef PubMed
320. Mouchiroud, L., Houtkooper, R. H. and Auwerx, J. (2013) NAD+ metabolism: a therapeutic target for age-related metabolic disease. Crit. Rev. Biochem. Mol. Biol. 48, 397-408 CrossRef PubMed
321. Canto, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., Fernandez-Marcos, P. J., Yamamoto, H., Andreux, P. A., Cettour-Rose, P. et al. (2012) The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838-847 CrossRef PubMed
322. Khan, N. A., Auranen, M., Paetau, I., Pirinen, E., Euro, L., Forsstrom, S., Pasila, L., Velagapudi, V., Carroll, C. J., Auwerx, J. and Suomalainen, A. (2014) Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol. Med. 6, 721-731 PubMed
323. van de Weijer, T., Phielix, E., Bilet, L., Williams, E. G., Ropelle, E. R., Bierwagen, A., Livingstone, R., Nowotny, P., Sparks, L. M., Paglialunga, S. et al. (2015) Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes 64, 1193-1201 CrossRef PubMed
324. Cerutti, R., Pirinen, E., Lamperti, C., Marchet, S., Sauve, A. A., Li, W., Leoni, V., Schon, E. A., Dantzer, F., Auwerx, J. et al. (2014) NAD+-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab. 19, 1042-1049 CrossRef PubMed