title: Functional, morphological, and apoptotic alterations in skeletal muscle of ARC deficient mice.
abstract: Apoptotic signaling plays an important role in the development and maintenance of healthy skeletal muscle. However, dysregulation of apoptotic signals in skeletal muscle is associated with atrophy and loss of function. Apoptosis repressor with caspase recruitment domain (ARC) is a potent anti-apoptotic protein that is highly expressed in skeletal muscle; however, its role in this tissue has yet to be elucidated. To investigate whether ARC deficiency has morphological, functional, and apoptotic consequences, skeletal muscle from 18 week-old wild-type and ARC knockout (KO) mice was studied. In red muscle (soleus), we found lower maximum tetanic force, as well as a shift towards a greater proportion of type II fibers in ARC KO mice. Furthermore, the soleus of ARC KO mice exhibited lower total, as well as fiber type-specific cross sectional area in type I and IIA fibers. Interestingly, these changes in ARC KO mice corresponded with increased DNA fragmentation, albeit independent of caspase or calpain activation. However, cytosolic fractions of red muscle from ARC KO mice had higher apoptosis inducing factor content, suggesting increased mitochondrial-mediated, caspase-independent apoptotic signaling. This was confirmed in isolated mitochondrial preparations, as mitochondria from skeletal muscle of ARC KO mice were more susceptible to calcium stress. Interestingly, white muscle from ARC KO mice showed no signs of altered apoptotic signaling or detrimental morphological differences. Results from this study suggest that even under basal conditions ARC influences muscle apoptotic signaling, phenotype, and function, particularly in slow and/or oxidative muscle.
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, ON, N2L3G1, Canada.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Mitchell
authors.forename: Ian C
authors.initials: IC
authors.lastname: Smith
authors.forename: Daniel
authors.initials: D
authors.lastname: Gamu
authors.forename: Stefan
authors.initials: S
authors.lastname: Donath
authors.forename: A Russell
authors.initials: AR
authors.lastname: Tupling
authors.forename: Joe
authors.initials: J
authors.lastname: Quadrilatero
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C491787:Nol3 protein, mouse; D017382:Reactive Oxygen Species; D002154:Calpain; D020169:Caspases; D002118:Calcium