Contractile activity-induced mitochondrial biogenesis and mTORC1.
In response to exercise training, or chronic contractile activity, mitochondrial content is known to be enriched within skeletal muscle. However, the molecular mechanisms that mediate this adaptation are incompletely defined. Recently, the protein complex, mammalian target of rapamycin complex 1 (mTORC1), has been identified to facilitate the expression of nuclear genes encoding mitochondrial proteins (NUGEMPs) in resting muscle cells via the interaction of the mTORC1 components, mTOR and raptor, the transcription factor Yin Yang 1, and peroxisome proliferator-activated receptor-γ coactivator-1α. It is currently unknown if this mechanism is operative during the increase in mitochondrial content that occurs within skeletal muscle with chronic contractile activity (CCA). Thus we employed a cell culture model of murine skeletal muscle and subjected the myotubes to CCA for 3 h per day for 4 consecutive days in the presence or absence of the mTORC1 inhibitor rapamycin. CCA produced increases in the mitochondrial markers cytochrome oxidase (COX) IV (2.5-fold), Tfam (1.5-fold), and COX activity (1.6-fold). Rapamycin-mediated inhibition of mTORC1 did not suppress these CCA-induced increases in mitochondrial proteins and organelle content. mTORC1 inhibition alone produced a selective upregulation of mitochondrial proteins (COX IV, Tfam), but diminished organelle state 3 respiration. CCA restored this impairment to normal. Our results suggest that mTORC1 activity is not integral for the increase in mitochondrial content elicited by CCA, but is required to maintain mitochondrial function and homeostasis in resting muscle.
Muscle Health Rsearch Centre, School of Kinesiology and Health Science, York Univ., Toronto, Ontario, M3J 1P3, Canada.
Heather N
HN
Carter
David A
DA
Hood
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D046912:Multiprotein Complexes; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus