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

David A. Hood, Giulia Uguccioni, Anna Vainshtein, Donna D'souza

10.1002/cphy.c100074

Source: Volume 1, Issue 3, July 2011

Published online: July 2011

Full Article on Wiley Online Library



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.

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

How to Cite

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