{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T02:45:39Z","timestamp":1788576339860,"version":"build-2803163510"},"reference-count":55,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T00:00:00Z","timestamp":1595548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AR060636"],"award-info":[{"award-number":["AR060636"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR060636"],"award-info":[{"award-number":["AR060636"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Limb\u2010girdle muscular dystrophy R1 (LGMD R1) is caused by mutations in the <jats:italic>CAPN3<\/jats:italic> gene and is characterized by progressive muscle loss, impaired mitochondrial function and reductions in the slow oxidative gene expression programme.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Myostatin is a negative regulator of muscle growth, and its inhibition improves the phenotype in several muscle wasting disorders.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The effect of genetic and pharmacological inhibition of myostatin signalling on the disease phenotype in a mouse model of LGMD R1 (<jats:italic>CAPN3<\/jats:italic> knockout mouse\u2010C3KO) was studied.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Inhibition of myostatin signalling in C3KO muscles resulted in significant muscle hypertrophy; however, there were no improvements in muscle strength and exacerbation of exercise intolerance concomitant with further reduction of muscle oxidative capacity was observed.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Inhibition of myostatin signalling is unlikely to be a valid therapeutic strategy for LGMD R1.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Limb\u2010girdle muscular dystrophy R1 (LGMD R1) is caused by mutations in the <jats:italic>CAPN3<\/jats:italic> gene and is characterized by progressive muscle loss, impaired mitochondrial function and reductions in the slow oxidative gene expression programme. There are currently no therapies available to patients. We sought to determine if induction of muscle growth, through myostatin inhibition, represents a viable therapeutic strategy for this disease. Myostatin is a negative regulator of muscle growth, and its inhibition improves the phenotype in several muscle wasting disorders. However, the effect of myostatin depends on the genetic and pathophysiological context and may not be efficacious in all contexts. We found that genetic inhibition of myostatin through overexpression of follistatin (an endogenous inhibitor of myostatin) in our LGMD R1 model (C3KO) resulted in 1.5\u2010 to 2\u2010fold increase of muscle mass for the majority of limb muscles. However, muscle strength was not improved and exercise intolerance was exacerbated. Pharmacological inhibition of myostatin, using an anti\u2010myostatin antibody, resulted in statistically significant increases in muscle mass; however, functional testing did not reveal changes in muscle strength nor endurance in treated C3KO mice. Histochemical and biochemical evaluation of follistatin overexpressing mice revealed a reduction in the percentage of oxidative fibres and decreased activation of AMP\u2010activated protein kinase signalling in transgenics compared to C3KO muscles. Our data suggest that muscle hypertrophy, induced by myostatin inhibition, leads to loss of oxidative capacity, which further compromises metabolically impaired C3KO muscles and thus is unlikely to be a valid strategy for treatment of LGMD R1.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp279943","type":"journal-article","created":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T05:54:17Z","timestamp":1594619657000},"page":"3927-3939","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Myostatin inhibition promotes fast fibre hypertrophy but causes loss of AMP\u2010activated protein kinase signalling and poor exercise tolerance in a model of limb\u2010girdle muscular dystrophy R1\/2A"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6242-1009","authenticated-orcid":false,"given":"Irina","family":"Kramerova","sequence":"first","affiliation":[{"name":"Department of Neurology David Geffen School of Medicine at UCLA  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masha","family":"Marinov","sequence":"additional","affiliation":[{"name":"Department of Neurology David Geffen School of Medicine at UCLA  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Owens","sequence":"additional","affiliation":[{"name":"Pfizer Inc.  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