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Mechanisms of Exercise‐Induced Mitochondrial Biogenesis in Skeletal Muscle: Implications for Health and Disease

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Abstract

Mitochondria have paradoxical functions within cells. Essential providers of energy for cellular survival, they are also harbingers of cell death (apoptosis). Mitochondria exhibit remarkable dynamics, undergoing fission, fusion, and reticular expansion. Both nuclear and mitochondrial DNA (mtDNA) encode vital sets of proteins which, when incorporated into the inner mitochondrial membrane, provide electron transport capacity for ATP production, and when mutated lead to a broad spectrum of diseases. Acute exercise can activate a set of signaling cascades in skeletal muscle, leading to the activation of the gene expression pathway, from transcription, to post‐translational modifications. Research has begun to unravel the important signals and their protein targets that trigger the onset of mitochondrial adaptations to exercise. Exercise training leads to an accumulation of nuclear‐ and mtDNA‐encoded proteins that assemble into functional complexes devoted to mitochondrial respiration, reactive oxygen species (ROS) production, the import of proteins and metabolites, or apoptosis. This process of biogenesis has important consequences for metabolic health, the oxidative capacity of muscle, and whole body fitness. In contrast, the chronic muscle disuse that accompanies aging or muscle wasting diseases provokes a decline in mitochondrial content and function, which elicits excessive ROS formation and apoptotic signaling. Research continues to seek the molecular underpinnings of how regular exercise can be used to attenuate these decrements in organelle function, maintain skeletal muscle health, and improve quality of life. © 2011 American Physiological Society. Compr Physiol 1:1119‐1134, 2011.

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Figure 1. Figure 1.

PGC‐1α‐mediated mitochondrial biogenesis. Action potentials originating at the α‐motoneuron propagate electrical activity along the sarcolemma of skeletal muscle. This electrical current is coupled to the release of Ca2+ from the sarcoplasmic reticulum. Increases in intracellular Ca2+ levels (1) activate Ca2+‐sensitive signaling pathways, including CaMK and (2) allow for the initiation of muscle contraction. Continuous muscle contractions promote the formation of reactive oxygen species (ROS) and alter energy levels resulting in the activation of AMPK. Contractile activity also results in the phosphorylation of additional kinases such as p38 MAPK. These signal transduction pathways target transcription factors and the coactivator, PGC‐1α. Activated transcription factors, such as NRF‐1, regulate the expression of nuclear genes‐encoding mitochondrial proteins (NUGEMPs), as well as the transcription and mRNA expression of PGC‐1α. Once translated, PGC‐1α binds to transcription factors (including NRF‐1) to also regulate NUGEMPs. Following transcription, the nascent mRNA is translocated to the cytosol for further modification. Specific sequences (i.e., AU‐rich elements) located in the 3′ untranslated region (UTR) serve as sites for RNA‐binding proteins (RBPs) and microRNA (miRNA) interaction, both of which can target the transcript for degradation. Stable mRNA products avoid the decay process, and are translated into functional proteins. Newly synthesized mitochondrially‐destined proteins are imported into the organelle via the translocase of the outer and inner membrane (TOM and TIM, respectively) complexes. Imported proteins may be transcription factors for mtDNA, such as Tfam. The induction of mtDNA transcription via Tfam increases the expression of proteins encoded by the mitochondrial genome that will join as subunits of complexes in the electron transport chain (ETC). PGC‐1α also enhances the transcription of additional mitochondrially‐destined proteins that become incorporated into the ETC once imported into the organelle. The coordinated expression of both the nuclear and mitochondrial genomes via PGC‐1α contributes to the expansion of the organelle network, and enhances the process of contraction‐induced mitochondrial biogenesis.

Figure 2. Figure 2.

Mitochondrially mediated apoptotic pathway. In response to oxidative stress, kinases such as JNK activate Bax/Bak and other Bcl‐2 family member proteins. Bax/Bak then translocate to the mitochondria where they oligomerize and insert into the mitochondrial outer membrane. Bax translocation induces mitochondrial permeabilization either via the permeability transition pore (mtPTP) or via formation of the MAC. The pores facilitate the rapid release of cytochrome c, apoptosis‐inducing factor (AIF), EndoG and Smac/DIABLO (Smac/D). All of these proteins can either directly or indirectly cause DNA fragmentation, ultimately inducing nuclear decay. The indirect pathway is caspase‐dependent and occurs upon the liberation of cytochrome c from the mitochondria. Cytochrome c then interacts with apoptotic protease‐activating factor 1 (APAF‐1), dATP as well as caspase 9 (casp9) to form the apoptosome. The apoptosome activates caspase 3 (casp3) which translocates into the nucleus and induces DNA fragmentation. AIF and Endo G induce cell death in a caspase‐independent manner, by inserting into the nucleus and causing DNA fragmentation directly. Bcl‐2 is localized to the mitochondrial outer membrane where it opposes pro‐apoptotic activity by (1) preventing Bax oligomerization and (2) prohibiting the release of proapoptotic factors. Heat shock protein 70 (HSP 70) is another apoptotic inhibitor that prevents apoptosis by directly inhibiting AIF‐induced chromatin condensation, or by disrupting the APAF‐1 and cytochrome c association, thus halting apoptosome formation. XIAP acts to inhibit DNA fragmentation by inhibiting caspase activity. The role of exercise in mediating changes in the expression, translocation and function of these proteins remains to be fully elucidated.



Figure 1.

PGC‐1α‐mediated mitochondrial biogenesis. Action potentials originating at the α‐motoneuron propagate electrical activity along the sarcolemma of skeletal muscle. This electrical current is coupled to the release of Ca2+ from the sarcoplasmic reticulum. Increases in intracellular Ca2+ levels (1) activate Ca2+‐sensitive signaling pathways, including CaMK and (2) allow for the initiation of muscle contraction. Continuous muscle contractions promote the formation of reactive oxygen species (ROS) and alter energy levels resulting in the activation of AMPK. Contractile activity also results in the phosphorylation of additional kinases such as p38 MAPK. These signal transduction pathways target transcription factors and the coactivator, PGC‐1α. Activated transcription factors, such as NRF‐1, regulate the expression of nuclear genes‐encoding mitochondrial proteins (NUGEMPs), as well as the transcription and mRNA expression of PGC‐1α. Once translated, PGC‐1α binds to transcription factors (including NRF‐1) to also regulate NUGEMPs. Following transcription, the nascent mRNA is translocated to the cytosol for further modification. Specific sequences (i.e., AU‐rich elements) located in the 3′ untranslated region (UTR) serve as sites for RNA‐binding proteins (RBPs) and microRNA (miRNA) interaction, both of which can target the transcript for degradation. Stable mRNA products avoid the decay process, and are translated into functional proteins. Newly synthesized mitochondrially‐destined proteins are imported into the organelle via the translocase of the outer and inner membrane (TOM and TIM, respectively) complexes. Imported proteins may be transcription factors for mtDNA, such as Tfam. The induction of mtDNA transcription via Tfam increases the expression of proteins encoded by the mitochondrial genome that will join as subunits of complexes in the electron transport chain (ETC). PGC‐1α also enhances the transcription of additional mitochondrially‐destined proteins that become incorporated into the ETC once imported into the organelle. The coordinated expression of both the nuclear and mitochondrial genomes via PGC‐1α contributes to the expansion of the organelle network, and enhances the process of contraction‐induced mitochondrial biogenesis.



Figure 2.

Mitochondrially mediated apoptotic pathway. In response to oxidative stress, kinases such as JNK activate Bax/Bak and other Bcl‐2 family member proteins. Bax/Bak then translocate to the mitochondria where they oligomerize and insert into the mitochondrial outer membrane. Bax translocation induces mitochondrial permeabilization either via the permeability transition pore (mtPTP) or via formation of the MAC. The pores facilitate the rapid release of cytochrome c, apoptosis‐inducing factor (AIF), EndoG and Smac/DIABLO (Smac/D). All of these proteins can either directly or indirectly cause DNA fragmentation, ultimately inducing nuclear decay. The indirect pathway is caspase‐dependent and occurs upon the liberation of cytochrome c from the mitochondria. Cytochrome c then interacts with apoptotic protease‐activating factor 1 (APAF‐1), dATP as well as caspase 9 (casp9) to form the apoptosome. The apoptosome activates caspase 3 (casp3) which translocates into the nucleus and induces DNA fragmentation. AIF and Endo G induce cell death in a caspase‐independent manner, by inserting into the nucleus and causing DNA fragmentation directly. Bcl‐2 is localized to the mitochondrial outer membrane where it opposes pro‐apoptotic activity by (1) preventing Bax oligomerization and (2) prohibiting the release of proapoptotic factors. Heat shock protein 70 (HSP 70) is another apoptotic inhibitor that prevents apoptosis by directly inhibiting AIF‐induced chromatin condensation, or by disrupting the APAF‐1 and cytochrome c association, thus halting apoptosome formation. XIAP acts to inhibit DNA fragmentation by inhibiting caspase activity. The role of exercise in mediating changes in the expression, translocation and function of these proteins remains to be fully elucidated.

References
 1. Abdelmohsen K, Lal A, Kim HH, Gorospe M. Posttranscriptional orchestration of an anti‐apoptotic program by HuR. Cell Cycle 6: 1288‐1288, 2007.
 2. Adhihetty PJ, Ljubicic V, Hood DA. Effect of chronic contractile activity on SS and IMF mitochondrial apoptotic susceptibility in skeletal muscle. Am J Physiol Endocrinol Metab 292: E748‐E755, 2007.
 3. Adhihetty PJ, Ljubicic V, Menzies KJ, Hood DA. Differential susceptibility of subsarcolemmal and intermyofibrillar mitochondria to apoptotic stimuli. Am J Physiol Cell Physiol 289: C994‐C1001, 2005.
 4. Adhihetty PJ, O'Leary MF, Chabi B, Wicks KL, Hood DA. Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle. J Appl Physiol 102: 1143‐1143, 2007.
 5. Adhihetty PJ, O'Leary MF, Hood DA. Mitochondria in skeletal muscle: Adaptable rheostats of apoptotic susceptibility. Exerc Sport Sci Rev 36: 116‐116, 2008.
 6. Adhihetty PJ, Taivassalo T, Haller RG, Walkinshaw DR, Hood DA. The effect of training on the expression of mitochondrial biogenesis‐ and apoptosis‐related proteins in skeletal muscle of patients with mtDNA defects. Am J Physiol Endocrinol Metab 293: E672‐E680, 2007.
 7. Adhihetty PJ, Uguccioni G, Leick L, Hidalgo J, Pilegaard H, Hood DA. The role of PGC‐1{alpha} on mitochondrial function and apoptotic susceptibility in muscle. Am J Physiol Cell Physiol 297: c217‐c225, 2009.
 8. Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z. Exercise stimulates Pgc‐1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem 280: 19587‐19587, 2005.
 9. Akimoto T, Sorg BS, Yan Z. Real‐time imaging of peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha promoter activity in skeletal muscles of living mice. Am J Physiol Cell Physiol 287: C790‐C796, 2004.
 10. Alconada A, Kubrich M, Moczko M, Honlinger A, Pfanner N. The mitochondrial receptor complex: The small subunit Mom8b/Isp6 supports association of receptors with the general insertion pore and transfer of preproteins. Mol Cell Biol 15: 6196‐6196, 1995.
 11. Allen DL, Roy RR, Edgerton VR. Myonuclear domains in muscle adaptation and disease. Muscle Nerve 22: 1350‐1350, 1999.
 12. Alway SE, Martyn JK, Ouyang J, Chaudhrai A, Murlasits ZS. Id2 expression during apoptosis and satellite cell activation in unloaded and loaded quail skeletal muscles. Am J Physiol Regul Integr Comp Physiol 284: R540‐R549, 2003.
 13. Amat R, Planavila A, Chen SL, Iglesias R, Giralt M, Villarroya F. SIRT1 controls the transcription of the peroxisome proliferator‐activated receptor‐gamma Co‐activator‐1alpha (PGC‐1alpha) gene in skeletal muscle through the PGC‐1alpha autoregulatory loop and interaction with MyoD. J Biol Chem 284: 21872‐21872, 2009.
 14. Arany Z. PGC‐1 coactivators and skeletal muscle adaptations in health and disease. Curr Opin Genet Dev 18: 426‐426, 2008.
 15. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO. Adaptations of skeletal muscle to exercise: Rapid increase in the transcriptional coactivator PGC‐1. FASEB J 16: 1879‐1879, 2002.
 16. Baker MJ, Frazier AE, Gulbis JM, Ryan MT. Mitochondrial protein‐import machinery: Correlating structure with function. Trends Cell Biol 17: 456‐456, 2007.
 17. Baldwin KM, Klinkerfuss GH, Terjung RL, Mole PA, Holloszy JO. Respiratory capacity of white, red, and intermediate muscle: Adaptative response to exercise. Am J Physiol 222: 373‐373, 1972.
 18. Becker T, Vogtle FN, Stojanovski D, Meisinger C. Sorting and assembly of mitochondrial outer membrane proteins. Biochem Biophys Acta 1777: 557‐557, 2008.
 19. Bengtsson J, Gustafsson T, Widegren U, Jansson E, Sundberg CJ. Mitochondrial transcription factor A and respiratory complex IV increase in response to exercise training in humans. Pflugers Arch 443: 61‐61, 2001.
 20. Blesa JR, Prieto‐Ruiz JA, Hernandez JM, Hernandez‐Yago J. NRF‐2 transcription factor is required for human TOMM20 gene expression. Gene 391: 198‐198, 2007.
 21. Blum JL, Samarel AM, Mestril R. Phosphorylation and binding of AUF1 to the 3′‐untranslated region of cardiomyocyte SERCA2 a mRNA. Am J Physiol Heart Circ Physiol 289: H2543‐H2550, 2005.
 22. Bohnert M, Pfanner N, Van Der LM. A dynamic machinery for import of mitochondrial precursor proteins. FEBS Lett 581: 2802‐2802, 2007.
 23. Bolender N, Sickmann A, Wagner R, Meisinger C, Pfanner N. Multiple pathways for sorting mitochondrial precursor proteins. EMBO Rep 9: 42‐42, 2008.
 24. Burch N, Arnold AS, Item F, Summermatter S, Brochmann Santana SG, Christe M, Boutellier U, Toigo M, Handschin C. Electric pulse stimulation of cultured murine muscle cells reproduces gene expression changes of trained mouse muscle. PLoS ONE 5: e10970, 2010.
 25. Cao W, Douglas MG. Biogenesis of ISP6, a small carboxyl‐terminal anchored protein of the receptor complex of the mitochondrial outer membrane. J Biol Chem 270: 5674‐5674, 1995.
 26. Cartoni R, Leger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Deriaz O, Zorzano A, Gobelet C, Kralli A, Russell AP. Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise. J Physiol 567: 349‐349, 2005.
 27. Chabi B, Ljubicic V, Menzies KJ, Huang JH, Saleem A, Hood DA. Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging Cell 7: 2‐2, 2008.
 28. Chacinska A, Van Der LM, Mehnert CS, Guiard B, Mick DU, Hutu DP, Truscott KN, Wiedemann N, Meisinger C, Pfanner N, Rehling P. Distinct forms of mitochondrial TOM‐TIM supercomplexes define signal‐dependent states of preprotein sorting. Mol Cell Biol 30: 307‐307, 2010.
 29. Chakkalakal JV, Miura P, Belanger G, Michel RN, Jasmin BJ. Modulation of utrophin A mRNA stability in fast versus slow muscles via an AU‐rich element and calcineurin signaling. Nucleic Acids Res 36: 826‐826, 2008.
 30. Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH. MAP kinases. Chem Rev 101: 2449‐2449, 2001.
 31. Clayton DA. Replication and transcription of vertebrate mitochondrial DNA. Annu Rev Cell Biol 7: 453‐453, 1991.
 32. Cogswell AM, Stevens RJ, Hood DA. Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Am J Physiol 264: C383‐C389, 1993.
 33. Connor MK, Irrcher I, Hood DA. 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: 15898‐15898, 2001.
 34. Connor MK, Takahashi M, Hood DA. Tissue‐specific stability of nuclear‐ and mitochondrially encoded mRNAs. Arch Biochem Biophys 333: 103‐103, 1996.
 35. Craig EE, Hood DA. Influence of aging on protein import into cardiac mitochondria. Am J Physiol 272: H2983‐H2988, 1997.
 36. David PS, Tanveer R, Port JD. FRET‐detectable interactions between the ARE binding proteins, HuR and p37AUF1. RNA 13: 1453‐1453, 2007.
 37. Dietmeier K, Honlinger A, Bomer U, Dekker PJ, Eckerskorn C, Lottspeich F, Kubrich M, Pfanner N. Tom5 functionally links mitochondrial preprotein receptors to the general import pore. Nature 388: 195‐195, 1997.
 38. Doller A, Pfeilschifter J, Eberhardt W. Signalling pathways regulating nucleo‐cytoplasmic shuttling of the mRNA‐binding protein HuR. Cell Signal 20: 2165‐2165, 2008.
 39. Dudley GA, Abraham WM, Terjung RL. Influence of exercise intensity and duration on biochemical adaptations in skeletal muscle. J Appl Physiol 53: 844‐844, 1982.
 40. Evans MJ, Scarpulla RC. NRF‐1: A trans‐activator of nuclear‐encoded respiratory genes in animal cells. Genes Dev 4: 1023‐1023, 1990.
 41. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79: 351‐351, 2010.
 42. Fan X, Hussien R, Brooks GA. H2 O2‐induced mitochondrial fragmentation in C2C12 myocytes. Free Radic Biol Med 49: 1646‐1646, 2010.
 43. Figueroa A, Cuadrado A, Fan J, Atasoy U, Muscat GE, Munoz‐Canoves P, Gorospe M, Munoz A. Role of HuR in skeletal myogenesis through coordinate regulation of muscle differentiation genes. Mol Cell Biol 23: 4991‐4991, 2003.
 44. Freyssenet D, Connor MK, Takahashi M, Hood DA. Cytochrome c transcriptional activation and mRNA stability during contractile activity in skeletal muscle. Am J Physiol 277: E26‐E32, 1999.
 45. Gibala MJ, McGee SL. Metabolic adaptations to short‐term high‐intensity interval training: A little pain for a lot of gain? Exerc Sport Sci Rev 36: 58‐58, 2008.
 46. Gleyzer N, Vercauteren K, Scarpulla RC. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF‐1 and NRF‐2) and PGC‐1 family coactivators. Mol Cell Biol 25: 1354‐1354, 2005.
 47. Gordon JW, Rungi AA, Inagaki H, Hood DA. Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle. J Appl Physiol 90: 389‐389, 2001.
 48. Gouble A, Morello D. Synchronous and regulated expression of two AU‐binding proteins, AUF1 and HuR, throughout murine development. Oncogene 19: 5377‐5377, 2000.
 49. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 305: 626‐626, 2004.
 50. Grey JY, Connor MK, Gordon JW, Yano M, Mori M, Hood DA. Tom20‐mediated mitochondrial protein import in muscle cells during differentiation. Am J Physiol Cell Physiol 279: C1393‐C1400, 2000.
 51. Grosshans H, Filipowicz W. Molecular biology: The expanding world of small RNAs. Nature 451: 414‐414, 2008.
 52. Guan HP, Ishizuka T, Chui PC, Lehrke M, Lazar MA. Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev 19: 453‐453, 2005.
 53. Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM. An autoregulatory loop controls peroxisome proliferator‐activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A 100: 7111‐7111, 2003.
 54. Handschin C, Spiegelman BM. Peroxisome proliferator‐activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27: 728‐728, 2006.
 55. Harman D. Free radical theory of aging: An update: Increasing the functional life span. Ann N Y Acad Sci 1067: 10‐10, 2006.
 56. Henriksson J, Reitman JS. Time course of changes in human skeletal muscle succinate dehydrogenase and cytochrome oxidase activities and maximal oxygen uptake with physical activity and inactivity. Acta Physiol Scand 99: 91‐91, 1977.
 57. Hernandez JM, Giner P, Hernandez‐Yago J. Gene structure of the human mitochondrial outer membrane receptor Tom20 and evolutionary study of its family of processed pseudogenes. Gene 239: 283‐283, 1999.
 58. Herzig S, Martinou JC. Mitochondrial dynamics: To be in good shape to survive. Curr Mol Med 8: 131‐131, 2008.
 59. Hofmann S, Rothbauer U, Muhlenbein N, Neupert W, Gerbitz KD, Brunner M, Bauer MF. The C66 W mutation in the deafness dystonia peptide 1 (DDP1) affects the formation of functional DDP1.TIM13 complexes in the mitochondrial intermembrane space. J Biol Chem 277: 23287‐23287, 2002.
 60. Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 242: 2278‐2278, 1967.
 61. Honlinger A, Bomer U, Alconada A, Eckerskorn C, Lottspeich F, Dietmeier K, Pfanner N. Tom7 modulates the dynamics of the mitochondrial outer membrane translocase and plays a pathway‐related role in protein import. EMBO J 15: 2125‐2125, 1996.
 62. Hood DA. Invited review: Contractile activity‐induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 90: 1137‐1137, 2001.
 63. Hood DA, Irrcher I, Ljubicic V, Joseph AM. Coordination of metabolic plasticity in skeletal muscle. J Exp Biol 209: 2265‐2265, 2006.
 64. Hoppeler H. Exercise‐induced ultrastructural changes in skeletal muscle. Int J Sports Med 7: 187‐187, 1986.
 65. Howald H, Hoppeler H, Claassen H, Mathieu O, Straub R. Influences of endurance training on the ultrastructural composition of the different muscle fiber types in humans. Pflugers Arch 403: 369‐369, 1985.
 66. Huang JH, Joseph AM, Ljubicic V, Iqbal S, Hood DA. Effect of age on the processing and import of matrix‐destined mitochondrial proteins in skeletal muscle. J Gerontol A Biol Sci Med Sci 65: 138‐138, 2010.
 67. Huo L, Scarpulla RC. Mitochondrial DNA instability and peri‐implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Mol Cell Biol 21: 644‐644, 2001.
 68. Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA. PPARgamma coactivator‐1alpha expression during thyroid hormone‐ and contractile activity‐induced mitochondrial adaptations. Am J Physiol Cell Physiol 284: C1669‐C1677, 2003.
 69. Irrcher I, Hood DA. Regulation of Egr‐1, SRF, and Sp1 mRNA expression in contracting skeletal muscle cells. J Appl Physiol 97: 2207‐2207, 2004.
 70. Irrcher I, Ljubicic V, Hood DA. Interactions between ROS and AMP kinase activity in the regulation of PGC‐1{alpha} transcription in skeletal muscle cells. Am J Physiol Cell Physiol 296: C116‐C123, 2009.
 71. Irrcher I, Ljubicic V, Kirwan AF, Hood DA. AMP‐activated protein kinase‐regulated activation of the PGC‐1alpha promoter in skeletal muscle cells. PLoS ONE 3: e3614, 2008.
 72. Joseph AM, Ljubicic V, Adhihetty PJ, Hood DA. 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, 2010.
 73. Joseph AM, Rungi AA, Robinson BH, Hood DA. Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects. Am J Physiol Cell Physiol 286: C867‐C875, 2004.
 74. Kassenbrock CK, Cao W, Douglas MG. Genetic and biochemical characterization of ISP6, a small mitochondrial outer membrane protein associated with the protein translocation complex. EMBO J 12: 3023‐3023, 1993.
 75. Klamt F, Zdanov S, Levine RL, Pariser A, Zhang Y, Zhang B, Yu LR, Veenstra TD, Shacter E. Oxidant‐induced apoptosis is mediated by oxidation of the actin‐regulatory protein cofilin. Nat Cell Biol 11: 1241‐1241, 2009.
 76. Koopman WJ, Verkaart S, Visch HJ, Van Der Westhuizen FH, Murphy MP, Van Den Heuvel LW, Smeitink JA, Willems PH. Inhibition of complex I of the electron transport chain causes O2−‐mediated mitochondrial outgrowth. Am J Physiol Cell Physiol 288: C1440‐C1450, 2005.
 77. Koopman WJ, Visch HJ, Verkaart S, Van Den Heuvel LW, Smeitink JA, Willems PH. Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency. Am J Physiol Cell Physiol 289: C881‐C890, 2005.
 78. Kutik S, Stojanovski D, Becker L, Becker T, Meinecke M, Kruger V, Prinz C, Meisinger C, Guiard B, Wagner R, Pfanner N, Wiedemann N. Dissecting membrane insertion of mitochondrial beta‐barrel proteins. Cell 132: 1011‐1011, 2008.
 79. Lai RY, Ljubicic V, D'souza D, Hood DA. Effect of chronic contractile activity on mRNA stability in skeletal muscle. Am J Physiol Cell Physiol 299: C155‐C163, 2010.
 80. Larsson NG, Oldfors A, Holme E, Clayton DA. Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion. Biochem Biophys Res Commun 200: 1374‐1374, 1994.
 81. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal‐Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP. PGC‐1alpha deficiency causes multi‐system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3: e101, 2005.
 82. Lin J, Wu PH, Tarr PT, Lindenberg KS, St‐Pierre J, Zhang CY, Mootha VK, Jager S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM. Defects in adaptive energy metabolism with CNS‐linked hyperactivity in PGC‐1alpha null mice. Cell 119: 121‐121, 2004.
 83. Ljubicic V, Adhihetty PJ, Hood DA. Application of animal models: Chronic electrical stimulation‐induced contractile activity. Can J Appl Physiol 30: 625‐625, 2005.
 84. Ljubicic V, Hood DA. Kinase‐specific responsiveness to incremental contractile activity in skeletal muscle with low and high mitochondrial content. Am J Physiol Endocrinol Metab 295: E195‐E204, 2008.
 85. Ljubicic V, Joseph AM, Saleem A, Uguccioni G, Collu‐Marchese M, Lai RY, Nguyen LM, Hood DA. Transcriptional and post‐transcriptional regulation of mitochondrial biogenesis in skeletal muscle: Effects of exercise and aging. Biochem Biophys Acta 1800: 223‐223, 2010.
 86. Martinus RD, Garth GP, Webster TL, Cartwright P, Naylor DJ, Hoj PB, Hoogenraad NJ. Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur J Biochem 240: 98‐98, 1996.
 87. McCulloch V, Seidel‐Rogol BL, Shadel GS. A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S‐adenosylmethionine. Mol Cell Biol 22: 1116‐1116, 2002.
 88. Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol A Biol Sci Med Sci 61: 534‐534, 2006.
 89. Michaelson LP, Shi G, Ward CW, Rodney GG. Mitochondrial redox potential during contraction in single intact muscle fibers. Muscle Nerve 42: 522‐522, 2010.
 90. Michel JB, Ordway GA, Richardson JA, Williams RS. Biphasic induction of immediate early gene expression accompanies activity‐dependent angiogenesis and myofiber remodeling of rabbit skeletal muscle. J Clin Invest 94: 277‐277, 1994.
 91. Moraes CT. What regulates mitochondrial DNA copy number in animal cells? Trends Genet 17: 199‐199, 2001.
 92. Murakami T, Shimomura Y, Yoshimura A, Sokabe M, Fujitsuka N. Induction of nuclear respiratory factor‐1 expression by an acute bout of exercise in rat muscle. Biochem Biophys Acta 1381: 113‐113, 1998.
 93. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. AMPK and PPARdelta agonists are exercise mimetics. Cell 134: 405‐405, 2008.
 94. Neufer PD, Ordway GA, Hand GA, Shelton JM, Richardson JA, Benjamin IJ, Williams RS. Continuous contractile activity induces fiber type specific expression of HSP70 in skeletal muscle. Am J Physiol 271: C1828‐C1837, 1996.
 95. Ogata T, Yamasaki Y. Ultra‐high‐resolution scanning electron microscopy of mitochondria and sarcoplasmic reticulum arrangement in human red, white, and intermediate muscle fibers. Anat Rec 248: 214‐214, 1997.
 96. Ojuka EO, Jones TE, Han DH, Chen M, Holloszy JO. Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle. FASEB J 17: 675‐675, 2003.
 97. Ongwijitwat S, Liang HL, Graboyes EM, Wong‐Riley MT. Nuclear respiratory factor 2 senses changing cellular energy demands and its silencing down‐regulates cytochrome oxidase and other target gene mRNAs. Gene 374: 39‐39, 2006.
 98. Ornatsky OI, Connor MK, Hood DA. Expression of stress proteins and mitochondrial chaperonins in chronically stimulated skeletal muscle. Biochem J 311: (Pt 1): 119‐119, 1995.
 99. Parisi MA, Clayton DA. Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science 252: 965‐965, 1991.
 100. Pette D, Wimmer M, Nemeth P. Do enzyme activities vary along muscle fibres? Histochemistry 67: 225‐225, 1980.
 101. Pilegaard H, Ordway GA, Saltin B, Neufer PD. Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. Am J Physiol Endocrinol Metab 279: E806‐E814, 2000.
 102. Pilegaard H, Saltin B, Neufer PD. Exercise induces transient transcriptional activation of the PGC‐1alpha gene in human skeletal muscle. J Physiol 546: 851‐851, 2003.
 103. Pogozelski AR, Geng T, Li P, Yin X, Lira VA, Zhang M, Chi JT, Yan Z. p38gamma mitogen‐activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice. PLoS ONE 4: e7934, 2009.
 104. Pollack M, Phaneuf S, Dirks A, Leeuwenburgh C. The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann N Y Acad Sci 959: 93‐93, 2002.
 105. Poulton J, Morten K, Freeman‐Emmerson C, Potter C, Sewry C, Dubowitz V, Kidd H, Stephenson J, Whitehouse W, Hansen FJ, Parisi M, Brown G. Deficiency of the human mitochondrial transcription factor h‐mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion. Hum Mol Genet 3: 1763‐1763, 1994.
 106. Powers SK, Jackson MJ. Exercise‐induced oxidative stress: Cellular mechanisms and impact on muscle force production. Physiol Rev 88: 1243‐1243, 2008.
 107. Powers SK, Kavazis AN, McClung JM. Oxidative stress and disuse muscle atrophy. J Appl Physiol 102: 2389‐2389, 2007.
 108. Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, O'Malley B, Spiegelman BM. Activation of PPARgamma coactivator‐1 through transcription factor docking. Science 286: 1368‐1368, 1999.
 109. Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, Krauss S, Mootha VK, Lowell BB, Spiegelman BM. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator‐1. Mol Cell 8: 971‐971, 2001.
 110. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold‐inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92: 829‐829, 1998.
 111. Reichmann H, Pette D. A comparative microphotometric study of succinate dehydrogenase activity levels in type I, IIA and IIB fibres of mammalian and human muscles. Histochemistry 74: 27‐27, 1982.
 112. Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Bluher M. Antioxidants prevent health‐promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106: 8665‐8665, 2009.
 113. Roesch K, Curran SP, Tranebjaerg L, Koehler CM. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8 a‐TIMM13 complex. Hum Mol Genet 11: 477‐477, 2002.
 114. Ross J. mRNA stability in mammalian cells. Microbiol Rev 59: 423‐423, 1995.
 115. Scarpulla RC. Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem 97: 673‐673, 2006.
 116. Scarpulla RC. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochem Biophys Acta 1576: 1‐1, 2002.
 117. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88: 611‐611, 2008.
 118. schenes‐Furry J, Angus LM, Belanger G, Mwanjewe J, Jasmin BJ. Role of ELAV‐like RNA‐binding proteins HuD and HuR in the post‐transcriptional regulation of acetylcholinesterase in neurons and skeletal muscle cells. Chem Biol Interact 157‐158: 43‐43, 2005.
 119. Schenes‐Furry J, Belanger G, Mwanjewe J, Lunde JA, Parks RJ, Perrone‐Bizzozero N, Jasmin BJ. The RNA‐binding protein HuR binds to acetylcholinesterase transcripts and regulates their expression in differentiating skeletal muscle cells. J Biol Chem 280: 25361‐25361, 2005.
 120. Singh K, Hood DA. Effect of denervation‐induced muscle disuse on mitochondrial protein import. Am J Physiol Cell Physiol 300: c138‐c145, 2010.
 121. Sirrenberg C, Bauer MF, Guiard B, Neupert W, Brunner M. Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22. Nature 384: 582‐582, 1996.
 122. Siu PM, Alway SE. Deficiency of the Bax gene attenuates denervation‐induced apoptosis. Apoptosis 11: 967‐967, 2006.
 123. Siu PM, Bryner RW, Murlasits Z, Alway SE. Response of XIAP, ARC, and FLIP apoptotic suppressors to 8 wk of treadmill running in rat heart and skeletal muscle. J Appl Physiol 99: 204‐204, 2005.
 124. Siu PM, Pistilli EE, Alway SE. Apoptotic responses to hindlimb suspension in gastrocnemius muscles from young adult and aged rats. Am J Physiol Regul Integr Comp Physiol 289: R1015‐R1026, 2005.
 125. Siu PM, Pistilli EE, Murlasits Z, Alway SE. Hindlimb unloading increases muscle content of cytosolic but not nuclear Id2 and p53 proteins in young adult and aged rats. J Appl Physiol 100: 907‐907, 2006.
 126. Siu PM, Wang Y, Alway SE. Apoptotic signaling induced by H2 O2‐mediated oxidative stress in differentiated C2C12 myotubes. Life Sci 84: 468‐468, 2009.
 127. Takahashi M, Chesley A, Freyssenet D, Hood DA. Contractile activity‐induced adaptations in the mitochondrial protein import system. Am J Physiol 274: C1380‐C1387, 1998.
 128. Takahashi M, Hood DA. Chronic stimulation‐induced changes in mitochondria and performance in rat skeletal muscle. J Appl Physiol 74: 934‐934, 1993.
 129. Takahashi M, Hood DA. Protein import into subsarcolemmal and intermyofibrillar skeletal muscle mitochondria. Differential import regulation in distinct subcellular regions. J Biol Chem 271: 27285‐27285, 1996.
 130. Tong X, Pelling JC. Enhancement of p53 expression in keratinocytes by the bioflavonoid apigenin is associated with RNA‐binding protein HuR. Mol Carcinog 48: 118‐118, 2009.
 131. Twig G, Hyde B, Shirihai OS. Mitochondrial fusion, fission and autophagy as a quality control axis: The bioenergetic view. Biochem Biophys Acta 1777: 1092‐1092, 2008.
 132. Van Der GK, Di‐Marco S, Clair E, Gallouzi IE. RNAi‐mediated HuR depletion leads to the inhibition of muscle cell differentiation. J Biol Chem 278: 47119‐47119, 2003.
 133. Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG. Coordination of p300‐mediated chromatin remodeling and TRAP/mediator function through coactivator PGC‐1alpha. Mol Cell 12: 1137‐1137, 2003.
 134. Weitzel JM, Iwen KA, Seitz HJ. Regulation of mitochondrial biogenesis by thyroid hormone. Exp Physiol 88: 121‐121, 2003.
 135. Williams RS. Mitochondrial gene expression in mammalian striated muscle. Evidence that variation in gene dosage is the major regulatory event. J Biol Chem 261: 12390‐12390, 1986.
 136. Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO. Activation of AMP‐activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 88: 2219‐2219, 2000.
 137. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC‐1. Cell 98: 115‐115, 1999.
 138. Xia Y, Buja LM, Scarpulla RC, McMillin JB. Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation. Proc Natl Acad Sci U S A 94: 11399‐11399, 1997.
 139. Yan Z, Li P, Akimoto T. Transcriptional control of the Pgc‐1alpha gene in skeletal muscle in vivo. Exerc Sport Sci Rev 35: 97‐97, 2007.
 140. Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A 103: 2653‐2653, 2006.

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David A. Hood, Giulia Uguccioni, Anna Vainshtein, Donna D'souza. Mechanisms of Exercise‐Induced Mitochondrial Biogenesis in Skeletal Muscle: Implications for Health and Disease. Compr Physiol 2011, 1: 1119-1134. doi: 10.1002/cphy.c100074