title: Age-related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S-nitrosylation that increase myofibril degradation and sarcopenia.
abstract: Sarcopenia, the age-related loss of muscle mass, is a highly-debilitating consequence of aging. In this investigation, we show sarcopenia is greatly reduced by muscle-specific overexpression of calpastatin, the endogenous inhibitor of calcium-dependent proteases (calpains). Further, we show that calpain cleavage of specific structural and regulatory proteins in myofibrils is prevented by covalent modification of calpain by nitric oxide (NO) through S-nitrosylation. We find that calpain in adult, non-sarcopenic muscles is S-nitrosylated but that aging leads to loss of S-nitrosylation, suggesting that reduced S-nitrosylation during aging leads to increased calpain-mediated proteolysis of myofibrils. Further, our data show that muscle aging is accompanied by loss of neuronal nitric oxide synthase (nNOS), the primary source of muscle NO, and that expression of a muscle-specific nNOS transgene restores calpain S-nitrosylation in aging muscle and prevents sarcopenia. Together, the findings show that in vivo reduction of calpain S-nitrosylation in muscle may be an important component of sarcopenia, indicating that modulation of NO can provide a therapeutic strategy to slow muscle loss during old age.
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095-1606, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Samengo
authors.forename: Anna
authors.initials: A
authors.lastname: Avik
authors.forename: Brian
authors.initials: B
authors.lastname: Fedor
authors.forename: Daniel
authors.initials: D
authors.lastname: Whittaker
authors.forename: Kyu H
authors.initials: KH
authors.lastname: Myung
authors.forename: Michelle
authors.initials: M
authors.lastname: Wehling-Henricks
authors.forename: James G
authors.initials: JG
authors.lastname: Tidball
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics*; D020033:Protein Isoforms / Q000378:metabolism; D059748:Proteolysis; D055948:Sarcopenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D002135:Calcium-Binding Proteins; D020033:Protein Isoforms; D009569:Nitric Oxide; C033668:calpastatin; D052248:Nitric Oxide Synthase Type I; D002154:Calpain