Age‐related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S‐nitrosylation that increase myofibril degradation and sarcopenia
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Summary: 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.
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Ageing is linked to altered synthesis of nitric oxide (NO) in skeletal muscle, which regulates FAP fate through inhibition of their differentiation into adipocytes.
“Ageing is also linked to altered synthesis of nitric oxide (NO) in skeletal muscle,[ 47 ] which regulates FAP fate through inhibition of their differentiation into adipocytes.”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [47]
nNOS missing from the dystrophin protein complex in skeletal muscle is associated with most forms of muscular dystrophies and likely also with sarcopenia.
“It is also known that nNOS missing from the dystrophin protein complex in the skeletal muscle is associated with most forms of muscular dystrophies and likely also with sarcopenia [23; 24].”
From Skeletal muscle as an endogenous nitrate reservoir (2015) · cites this paper as [24]
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- Authors
- Samengo, G., Avik, A., Fedor, B., Whittaker, D., Myung, K. H., Wehling‐Henricks, M., & Tidball, J. G.
- Affiliations
- University of California, Los Angeles (US)
- Chonnam National University (KR)
- Corresponding author
- Tidball, James G.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-10-04
- Volume
- 11
- Issue
- 6
- Pages
- 1036-1045
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3734855
- OpenAlex
- W1981200316
- Cited by
- 95
- References
- 46
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 10 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 11 · 2017: 4 · 2016: 9 · 2015: 12 · 2014: 4 · 2013: 4
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG041147)
- National Institute of General Medical Sciences (T32GM065823)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054451)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Keywords
- sarcopenia, muscle aging, neuronal nitric oxide synthase, calpastatin, myofibril degradation, calpain-mediated proteolysis, nitric oxide, skeletal muscle
- MeSH terms
- Aging, Animals, Calcium-Binding Proteins, Calpain, Humans, Myofibrils, Nitric Oxide, Gene Expression, Muscle, Skeletal, Protein Isoforms, Mice, Nitric Oxide Synthase Type I, Sarcopenia, Proteolysis
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