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Department of Kinesiology and Health Science and Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3
Chronic contractile activity produces mitochondrial biogenesis in muscle. This adaptation results in a significant shift in adenine nucleotide metabolism, with attendant improvements in fatigue resistance. The vast majority of mitochondrial proteins are derived from the nuclear genome, necessitating the transcription of genes, the translation of mRNA into protein, the targeting of the protein to a mitochondrial compartment via the import machinery, and the assembly of multisubunit enzyme complexes in the respiratory chain or matrix. Putative signals involved in initiating this pathway of gene expression in response to contractile activity likely arise from combinations of accelerations in ATP turnover or imbalances between mitochondrial ATP synthesis and cellular ATP demand, and Ca2+ fluxes. These rapid events are followed by the activation of exercise-responsive kinases, which phosphorylate proteins such as transcription factors, which subsequently bind to upstream regulatory regions in DNA, to alter transcription rates. Contractile activity increases the mRNA levels of nuclear-encoded proteins such as cytochrome c and mitochondrial transcription factor A (Tfam) and mRNA levels of upstream transcription factors like c-jun and nuclear respiratory factor-1 (NRF-1). mRNA level changes are often most evident during the postexercise recovery period, and they can occur as a result of contractile activity-induced increases in transcription or mRNA stability. Tfam is imported into mitochondria and controls the expression of mitochondrial DNA (mtDNA). mtDNA contributes only 13 protein products to the respiratory chain, but they are vital for electron transport and ATP synthesis. Contractile activity increases Tfam expression and accelerates its import into mitochondria, resulting in increased mtDNA transcription and replication. The result of this coordinated expression of the nuclear and the mitochondrial genomes, along with poorly understood changes in phospholipid synthesis, is an expansion of the muscle mitochondrial reticulum. Further understanding of 1) regulation of mtDNA expression, 2) upstream activators of NRF-1 and other transcription factors, 3) the identity of mRNA stabilizing proteins, and 4) potential of contractile activity-induced changes in apoptotic signals are warranted.
muscle gene expression; signal transduction; adaptation; exercise; mitochondrial DNA
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 C. M. Stary, O. Mathieu-Costello, and M. C. Hogan Resistance to fatigue of individual Xenopus single skeletal muscle fibres is correlated with mitochondrial volume density Exp Physiol, September 1, 2004; 89(5): 617 - 621. [Abstract] [Full Text] [PDF]
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P. J. LeBlanc, S. J. Peters, R. J. Tunstall, D. Cameron-Smith, and G. J. F. Heigenhauser Effects of aerobic training on pyruvate dehydrogenase and pyruvate dehydrogenase kinase in human skeletal muscle J. Physiol., June 1, 2004; 557(2): 559 - 570. [Abstract] [Full Text] [PDF]
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T. E. Sheehan, P. A. Kumar, and D. A. Hood Tissue-specific regulation of cytochrome c oxidase subunit expression by thyroid hormone Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E968 - E974. [Abstract] [Full Text] [PDF]
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D. Freyssenet, I. Irrcher, M. K. Connor, M. Di Carlo, and D. A. Hood Calcium-regulated changes in mitochondrial phenotype in skeletal muscle cells Am J Physiol Cell Physiol, May 1, 2004; 286(5): C1053 - C1061. [Abstract] [Full Text] [PDF]
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S. Terada and I. Tabata Effects of acute bouts of running and swimming exercise on PGC-1{alpha} protein expression in rat epitrochlearis and soleus muscle Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E208 - E216. [Abstract] [Full Text] [PDF]
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M. Lucassen, A. Schmidt, L. G. Eckerle, and H.-O. Portner Mitochondrial proliferation in the permanent vs. temporary cold: enzyme activities and mRNA levels in Antarctic and temperate zoarcid fish Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2003; 285(6): R1410 - R1420. [Abstract] [Full Text] [PDF]
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A. L. Hildebrandt, H. Pilegaard, and P. D. Neufer Differential transcriptional activation of select metabolic genes in response to variations in exercise intensity and duration Am J Physiol Endocrinol Metab, November 1, 2003; 285(5): E1021 - E1027. [Abstract] [Full Text] [PDF]
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K. BAAR, Z. SONG, C. F. SEMENKOVICH, T. E. JONES, D.-H. HAN, L. A. NOLTE, E. O. OJUKA, M. CHEN, and J. O. HOLLOSZY Skeletal muscle overexpression of nuclear respiratory factor 1 increases glucose transport capacity FASEB J, September 1, 2003; 17(12): 1666 - 1673. [Abstract] [Full Text] [PDF]
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C. R. Bruce, A. L. Carey, J. A. Hawley, and M. A. Febbraio Intramuscular Heat Shock Protein 72 and Heme Oxygenase-1 mRNA Are Reduced in Patients With Type 2 Diabetes: Evidence That Insulin Resistance Is Associated With a Disturbed Antioxidant Defense Mechanism Diabetes, September 1, 2003; 52(9): 2338 - 2345. [Abstract] [Full Text] [PDF]
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C. Handschin, J. Rhee, J. Lin, P. T. Tarr, and B. M. Spiegelman An autoregulatory loop controls peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} expression in muscle PNAS, June 10, 2003; 100(12): 7111 - 7116. [Abstract] [Full Text] [PDF]
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I. Irrcher, P. J. Adhihetty, T. Sheehan, A.-M. Joseph, and D. A. Hood PPARgamma coactivator-1alpha expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations Am J Physiol Cell Physiol, June 1, 2003; 284(6): C1669 - C1677. [Abstract] [Full Text] [PDF]
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S. Welle, K. Bhatt, B. Shah, N. Needler, J. M. Delehanty, and C. A. Thornton Reduced amount of mitochondrial DNA in aged human muscle J Appl Physiol, April 1, 2003; 94(4): 1479 - 1484. [Abstract] [Full Text] [PDF]
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S. L. McGee, K. F. Howlett, R. L. Starkie, D. Cameron-Smith, B. E. Kemp, and M. Hargreaves Exercise Increases Nuclear AMPK {alpha}2 in Human Skeletal Muscle Diabetes, April 1, 2003; 52(4): 926 - 928. [Abstract] [Full Text] [PDF]
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H. Pilegaard, B. Saltin, and P D. Neufer Exercise induces transient transcriptional activation of the PGC-1{alpha} gene in human skeletal muscle J. Physiol., February 1, 2003; 546(3): 851 - 858. [Abstract] [Full Text] [PDF]
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B. Drew, S. Phaneuf, A. Dirks, C. Selman, R. Gredilla, A. Lezza, G. Barja, and C. Leeuwenburgh Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R474 - R480. [Abstract] [Full Text] [PDF]
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H. Zong, J. M. Ren, L. H. Young, M. Pypaert, J. Mu, M. J. Birnbaum, and G. I. Shulman AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation PNAS, December 10, 2002; 99(25): 15983 - 15987. [Abstract] [Full Text] [PDF]
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K. BAAR, A. R. WENDE, T. E. JONES, M. MARISON, L. A. NOLTE, M. CHEN, D. P. KELLY, and J. O. HOLLOSZY Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1 FASEB J, December 1, 2002; 16(14): 1879 - 1886. [Abstract] [Full Text] [PDF]
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M. A Febbraio, P. Ott, H. B. Nielsen, A. Steensberg, C. Keller, P. Krustrup, N. H Secher, and B. K. Pedersen Exercise induces hepatosplanchnic release of heat shock protein 72 in humans J. Physiol., November 1, 2002; 544(3): 957 - 962. [Abstract] [Full Text] [PDF]
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B. F. Miller, J. A. Fattor, K. A. Jacobs, M. A. Horning, S.-H. Suh, F. Navazio, and G. A. Brooks Metabolic and cardiorespiratory responses to "the lactate clamp" Am J Physiol Endocrinol Metab, November 1, 2002; 283(5): E889 - E898. [Abstract] [Full Text] [PDF]
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F. W Booth, M. V Chakravarthy, and E. E Spangenburg Exercise and gene expression: physiological regulation of the human genome through physical activity J. Physiol., September 1, 2002; 543(2): 399 - 411. [Abstract] [Full Text] [PDF]
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J Zoll, H Sanchez, B N'Guessan, F Ribera, E Lampert, X Bigard, B Serrurier, D Fortin, B Geny, V Veksler, et al. Physical activity changes the regulation of mitochondrial respiration in human skeletal muscle J. Physiol., August 15, 2002; 543(1): 191 - 200. [Abstract] [Full Text] [PDF]
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H. Hoppeler and M. Fluck Normal mammalian skeletal muscle and its phenotypic plasticity J. Exp. Biol., August 1, 2002; 205(15): 2143 - 2152. [Abstract] [Full Text] [PDF]
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F. W. Booth, M. V. Chakravarthy, S. E. Gordon, and E. E. Spangenburg Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy J Appl Physiol, July 1, 2002; 93(1): 3 - 30. [Abstract] [Full Text] [PDF]
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R. J. Tunstall, K. A. Mehan, G. D. Wadley, G. R. Collier, A. Bonen, M. Hargreaves, and D. Cameron-Smith Exercise training increases lipid metabolism gene expression in human skeletal muscle Am J Physiol Endocrinol Metab, July 1, 2002; 283(1): E66 - E72. [Abstract] [Full Text] [PDF]
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K. Sahlin, M. Fernstrom, M. Svensson, and M. Tonkonogi No evidence of an intracellular lactate shuttle in rat skeletal muscle J. Physiol., June 1, 2002; 541(2): 569 - 574. [Abstract] [Full Text] [PDF]
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 H. Wu, S. B. Kanatous, F. A. Thurmond, T. Gallardo, E. Isotani, R. Bassel-Duby, and R. S. Williams Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK Science, April 12, 2002; 296(5566): 349 - 352. [Abstract] [Full Text] [PDF]
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S. Duguez, L. Feasson, C. Denis, and D. Freyssenet Mitochondrial biogenesis during skeletal muscle regeneration Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E802 - E809. [Abstract] [Full Text] [PDF]
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