title: Induction of mitochondrial biogenesis protects against caspase-dependent and caspase-independent apoptosis in L6 myoblasts.
abstract: Apoptotic signaling plays an important role in skeletal muscle degradation, atrophy, and dysfunction. Mitochondria are central executers of apoptosis by directly participating in caspase-dependent and caspase-independent cell death signaling. Given the important apoptotic role of mitochondria, altering mitochondrial content could influence apoptosis. Therefore, we examined the direct effect of modest, but physiological increases in mitochondrial biogenesis and content on skeletal muscle apoptosis using a cell culture approach. Treatment of L6 myoblasts with SNAP or AICAR (5h/day for 5days) significantly increased PGC-1, AIF, cytochrome c, and MnSOD protein content as well as MitoTracker staining. Following induction of mitochondrial biogenesis, L6 myoblasts displayed decreased sensitivity to apoptotic cell death as well as reduced caspase-3 and caspase-9 activation following exposure to staurosporine (STS) and C2-ceramide. L6 myoblasts with higher mitochondrial content also exhibited reduced apoptosis and AIF release following exposure to hydrogen peroxide (H2O2). Analysis of several key apoptosis regulatory proteins (ARC, Bax, Bcl-2, XIAP), antioxidant proteins (catalase, MnSOD, CuZnSOD), and reactive oxygen species (ROS) measures (DCF and MitoSOX fluorescence) revealed that these mechanisms were not responsible for the observed cellular protection. However, myoblasts with higher mitochondrial content were less sensitive to Ca(2+)-induced mitochondrial permeability transition pore formation (mPTP) and mitochondrial membrane depolarization. Collectively, these data demonstrate that increased mitochondrial content at physiological levels provides protection against apoptotic cell death by decreasing caspase-dependent and caspase-independent signaling through influencing mitochondrial Ca(2+)-mediated apoptotic events. Therefore, increasing mitochondrial biogenesis/content may represent a potential therapeutic approach in skeletal muscle disorders displaying increased apoptosis.
authors: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors: Aaron D
authors: AD
authors: Dam
authors: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors: Andrew S
authors: AS
authors: Mitchell
authors: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada. Electronic address: jquadril@uwaterloo.ca.
authors: Joe
authors: J
authors: Quadrilatero
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D063269:Mitochondrial Turnover / Q000187:drug effects; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism; D011419:Propidium / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013194:Staining and Labeling
chemical_list: D017304:Annexin A5; D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011419:Propidium; D026423:S-Nitroso-N-Acetylpenicillamine; D020169:Caspases; C031143:AICA ribonucleotide; D002118:Calcium
keywords: AICAR; Apoptosis inducing factor; Cell death; Mitochondrium; SNAP; Skeletal muscle