Age-related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S-nitrosylation that increase myofibril degradation and sarcopenia
Giuseppina Samengo
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorAnna Avik
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorBrian Fedor
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorDaniel Whittaker
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorKyu H. Myung
Animal Science Department, Chonnam National University, Gwangju, Korea
Search for more papers by this authorMichelle Wehling-Henricks
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorCorresponding Author
James G. Tidball
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA, USA
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA
Correspondence:
James G. Tidball, Molecular, Cellular & Integrative Physiology Program
University of California, Los Angeles, CA 90095-1606, USA. Tel.: +1 310 206 3395; fax: +1 310 825 8489; e-mail: [email protected]
Search for more papers by this authorGiuseppina Samengo
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorAnna Avik
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorBrian Fedor
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorDaniel Whittaker
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorKyu H. Myung
Animal Science Department, Chonnam National University, Gwangju, Korea
Search for more papers by this authorMichelle Wehling-Henricks
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Search for more papers by this authorCorresponding Author
James G. Tidball
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA, USA
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA
Correspondence:
James G. Tidball, Molecular, Cellular & Integrative Physiology Program
University of California, Los Angeles, CA 90095-1606, USA. Tel.: +1 310 206 3395; fax: +1 310 825 8489; e-mail: [email protected]
Search for more papers by this authorSummary
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.
Supporting Information
| Filename | Description |
|---|---|
| acel12003-sup-0001-FigS1.pdfapplication/PDF, 763.5 KB | Fig. S1 Caspase-3 activation increases in aging skeletal muscle in vivo and S-nitrosylation inhibits caspase-3 proteolysis of MyHC-2b in purified myofibrils. |
| acel12003-sup-0002-SupplementData.docWord document, 37.5 KB | Data S1 Experimental procedures. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- Altun M, Besche HC, Overkleeft HS, Piccirillo R, Edelmann MJ, Kessler BM, Goldberg AL, Ulfhake B (2010) Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway. J. Biol. Chem. 285, 39597–39608.
- Communal C, Sumandea M, de Tombe P, Narula J, Solaro RJ, Hajjar RJ (2002) Functional consequences of caspase activation in cardiac myocytes. Proc. Natl. Acad. Sci. U.S.A. 99, 6252–6256.
- Costelli P, Tullio RD, Baccino FM, Melloni E (2001) Activation of Ca(2 + )-dependent proteolysis in skeletal muscle and heart in cancer cachexia. Br. J. Cancer 84, 946–950.
- D'Angelo MG, Gandossini S, Martinelli Boneschi F, Sciorati C, Bonato S, Brighina E, Comi GP, Turconi AC, Magri F, Stefanoni G, Brunelli S, Bresolin N, Cattaneo D, Clementi E (2012) Nitric oxide donor and non steroidal anti inflammatory drugs as a therapy for muscular dystrophies: evidence from a safety study with pilot efficacy measures in adult dystrophic patients. Pharmacol. Res. 65, 472–479.
- Dargelos E, Brulé C, Combaret L, Hadj-Sassi A, Dulong S, Poussard S, Cottin P (2007) Involvement of the calcium-dependent proteolytic system in skeletal muscle aging. Exp. Gerontol. 42, 1088–1098.
- Dayton WR, Reville WJ, Goll DE, Stromer MH (1976) A Ca2+-activated protease possibly involved in myofibrillar protein turnover. Partial characterization of the purified enzyme. Biochem. 15, 2159–2167.
- Du J, Wang X, Miereles C, Bailey JL, Debigare R, Zheng B, Price SR, Mitch WE (2004) Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J. Clin. Invest. 113, 115–123.
- Evans W (1997) Functional and metabolic consequences of sarcopenia. J. Nutr. 127, 998S–1003S.
- Ferrington DA, Krainev AG, Bigelow DJ (1998) Altered turnover of calcium regulatory proteins of the sarcoplasmic reticulum in aged skeletal muscle. J. Biol. Chem. 273, 5885–5891.
- Forrester MT, Foster MW, Benhar M, Stamler JS (2009) Detection of protein S-nitrosylation with the biotin-switch technique. Meth. Free Radical Biol. Med. 46, 119–126.
- Fraysse B, Desaphy JF, Rolland JF, Pierno S, Liantonio A, Giannuzzi V, Camerino C, Didonna MP, Cocchi D, De Luca A, et al. (2006) Fiber type-related changes in rat skeletal muscle calcium homeostasis during aging and restoration by growth hormone. Neurobiol. Dis. 21, 372–380.
- Ghaly A, Marsh DR (2010) Aging-associated oxidative stress modulates the acute inflammatory response in skeletal muscle after contusion injury. Exp. Gerontol. 45, 381–388.
- Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The calpain system. Physiol. Rev. 83, 731–801.
- Gutmann E, Hanzlikova V (1965) Age changes of motor endplates in muscle fibres of the rat. Gerontologia 11, 12–24.
- Holloszy JO, Chen M, Cartee GD, Young JC (1991) Skeletal muscle atrophy in old rats: differential changes in the three fiber types. Mech. Ageing Dev. 60, 199–213.
- Hotchkiss RS, Karl IE (1994) Dantrolene ameliorates the metabolic hallmarks of sepsis in rats and improves survival in a mouse model of endotoxemia. Proc. Natl. Acad. Sci. U.S.A. 91, 3039–3043.
- Ingalls CP, Warren GL, Armstrong RB (1999) Intracellular Ca2+ transients in mouse soleus muscle after hindlimb unloading and reloading. J. Appl. Physiol. 87, 386–390.
- Ishiura S, Sugita H, Suzuki K, Imahori K (1979) Studies of a calcium-activated neutral protease from chicken skeletal muscle. II. Substrate specificity. J. Biochem. 86, 579–581.
- Koh TJ, Tidball JG (2000) Nitric oxide inhibits calpain-mediated proteolysis of talin in skeletal muscle cells. Am. J. Physiol. 279, C806–C812.
- Liu Z, Cao C, Gao X, Ma Q, Ren J, Xue Y (2011) GPS-CCD: GPS-CCD: A novel computational program for the prediction of calpain cleavage sites. PLoS ONE 6, e19001.
- Maejima Y, Susumu A, Morikawa K, Ito H, Isobe M (2005) Nitric oxide inhibits myocardial apoptosis by preventing caspase-3 activity via S-nitrosylation. J. Mol. Cell. Cardiol. 38, 163–174.
- McGinnis KM, Gnegy ME, Park YH, Mukerjee N, Wang KK (1999) Procaspase-3 and poly(ADP)ribose polymerase (PARP) are calpain substrates. Biochem. Biophys. Res. Commun. 263, 94–99.
- Meng H, Leddy JJ, Holland P, Tuana BS (1996) The association of cardiac dystrophin with myofibrils/Z-disc regions in cardiac muscle suggests a novel role in the contractile apparatus. J. Biol. Chem. 271, 12364–12371.
- Nelson WB, Smuder AJ, Hudson MB, Talbert EE, Powers SK (2012) Cross-talk between the calpain and caspase-3 proteolytic systems in the diaphragm during prolonged mechanical ventilation. Crit. Care Med. 40, 1857–1863.
- Nguyen HX, Tidball JG (2003) Expression of a muscle-specific, nitric oxide synthase transgene prevents muscle membrane injury and reduces muscle inflammation during modified muscle use in mice. J. Physiol. 550, 347–356.
- Reddy MK, Etlinger JD, Rabinowitz M, Fischman DA, Zak R (1975) Removal of Z-lines and alpha-actinin from isolated myofibrils by a calcium-activated neutral protease. J. Biol. Chem. 250, 4278–4284.
- Renganathan M, Messi ML, Delbono O (1997) Dihydropyridine receptor-ryanodine receptor uncoupling in aged skeletal muscle. J. Membr. Biol. 157, 247–253.
- Rossig L, Fichtlscherer B, Breitschopf K, Haendeler J, Zeiher AM, Mulsch A, Dimmeler S (1999) Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J. Biol. Chem. 274, 6823–6826.
- Sellman JE, DeRuisseau KC, Betters JL, Lira VA, Soltow QA, Selsby JT, Criswell DS (2006) In vivo inhibition of nitric oxide synthase impairs upregulation of contractile protein mRNA in overloaded plantaris muscle. J. Appl. Physiol. 100, 258–265.
- Shiao T, Fond A, Deng B, Wehling-Henricks M, Adams ME, Froehner SC, Tidball JG (2004) Defects in neuromuscular junction structure in dystrophic muscle are corrected by expression of a NOS transgene in dystrophin-deficient muscles, but not in muscles lacking alpha- and beta1-syntrophins. Human Mol. Genet. 13, 1873–1884.
- Smuder AJ, Kavazis AN, Hudson MB, Nelson WB, Powers SK (2010) Oxidation enhances myofibrillar protein degradation via calpain and caspase-3. Free Radic. Biol. Med. 49, 1152–1160.
- Solomon V, Goldberg AL (1996) Importance of the ATP-ubiquitin-proteasome pathway in the degradation of soluble and myofibrillar proteins in rabbit muscle extracts. J. Biol. Chem. 271, 26690–26697.
- Supinski GS, Wang W, Callahan LA (2009) Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness. J. Appl. Physiol. 107, 1389–1396.
- Suzuki N, Motohashi N, Uezumi A, Fukada S, Yoshimura T, Itoyama Y, Aoki M, Miyagoe-Suzuki Y, Takeda S (2007) NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. J. Clin. Invest. 117, 2468–2476.
- Tidball JG, Spencer M (2002) Expression of a calpastatin transgene slows muscle wasting and obviates changes in myosin isoform expression during murine muscle disuse. J. Physiol. 545, 819–828.
- Tidball JG, Lavergne E, Lau KS, Spencer MJ, Stull JT, Wehling M (1998) Mechanical loading regulates NOS expression and activity in developing and adult skeletal muscle. Amer. J. Physiol. 275, C260–C266.
- Villalta SA, Rinaldi C, Deng B, Liu G, Fedor B, Tidball JG (2011) Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype. Human Mol. Genet. 20, 790–805.
- Volpi E, Nazemi R, Fujita S (2004) Muscle tissue changes with aging. Curr. Opin. Clin. Nutr. Metab. Care 7, 405–410.
- Wang KK, Posmantur R, Nadimpalli R, Nath R, Mohan P, Nixon RA, Talanian RV, Keegan M, Herzog L, Allen H (1998) Caspase-mediated fragmentation of calpain inhibitor protein calpastatin during apoptosis. Arch. Biochem. Biophys. 356, 187–196.
- Wehling M, Spencer M, Tidball JG (2001) A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. J. Cell Biol. 155, 123–131.
- Wei W, Fareed MU, Evenson A, Menconi MJ, Yang H, Petkova V, Hasselgren P (2004) Sepsis stimulates calpain activity in skeletal muscle by decreasing calpastatin activity but does not activate caspase-3. Am. J. Physiol. 288, R580–R590.
- Williams AB, Decourten-Myers GM, Fischer JE, Luo G, Sun X, Hasselgren PO (1999) Sepsis stimulates release of myofilaments in skeletal muscle by a calcium-dependent mechanism. FASEB J. 13, 1435–1443.
