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This condition arises from a combination of factors including reduced physical activity, insufficient protein intake, hyperphosphatemia, chronic inflammation, and uremia itself; however, the underlying molecular mechanisms remain poorly understood. Proteolysis in skeletal muscle is primarily controlled by the ubiquitin\u2013proteasome system, autophagy\u2013lysosome system, and calpains (CAPNs) cysteine proteases, which degrade structural proteins and mediate cell signaling. This study aims to investigate the role of CAPNs in CKD-associated muscle deterioration. CKD was induced in mice through an adenine-rich diet for 2, 4 and 6 weeks. The involvement of CAPNs in CKD-related sarcopenia was assessed using mice that overexpressed the CAPNs endogenous inhibitor, calpastatin (CAST). Gastrocnemius muscle strength, structural integrity, and function were evaluated. Mice with CKD showed elevated CAPNs, particularly CAPN2, expression and activity in the gastrocnemius, in parallel with significant muscle deterioration, including strength loss, structural damage, and impaired muscle performance. Overexpression of CAST prevented muscle strength loss, improved muscle function and structure without affecting renal function, and reversed fibrosis, inflammation and adipogenesis expression markers. Targeting CAPN2 could be a promising therapeutic strategy to mitigate muscle damage and improve physical performance in CKD patients.<\/jats:p>","DOI":"10.3390\/cells14231846","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:24:17Z","timestamp":1763979857000},"page":"1846","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role of Calpains in Uremia-Related Functional and Structural Muscle Changes: Protective Effect of Calpastatin Overexpression"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8144-6909","authenticated-orcid":false,"given":"Elena","family":"Guti\u00e9rrez-Calabr\u00e9s","sequence":"first","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5182-6396","authenticated-orcid":false,"given":"Sof\u00eda","family":"Campillo","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2550-0293","authenticated-orcid":false,"given":"Elena","family":"Alcalde-Est\u00e9vez","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8726-760X","authenticated-orcid":false,"given":"Paula","family":"Cuevas-Delgado","sequence":"additional","affiliation":[{"name":"Centre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEU, 28871 Boadilla del Monte, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4722-491X","authenticated-orcid":false,"given":"Coral","family":"Barbas","sequence":"additional","affiliation":[{"name":"Centre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEU, 28871 Boadilla del Monte, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Garc\u00eda-Villoria","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alba","family":"Silvestre-Vargas","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Griera","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1225-5911","authenticated-orcid":false,"given":"Sergio","family":"de Frutos","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda P.","family":"Ruiz-Torres","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Rodr\u00edguez-Puyol","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"},{"name":"Department of Medicine and Medical Specialties, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Biomedical Research Foundation and Nephrology Unit, Hospital Universitario Pr\u00edncipe de Asturias, 28871 Alcal\u00e1 de Henares, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7739-1319","authenticated-orcid":false,"given":"Laura","family":"Calleros","sequence":"additional","affiliation":[{"name":"Physiology Unit, Department of Systems Biology, Universidad de Alcal\u00e1, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Fundaci\u00f3n Renal Espa\u00f1ola, 28871 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28871 Madrid, Spain"},{"name":"INNOREN-CM, 28871 Madrid, Spain"},{"name":"RICORS2040 Kidney Disease, Instituto de Salud Carlos III, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"990S","DOI":"10.1093\/jn\/127.5.990S","article-title":"Sarcopenia: Origins and Clinical Relevance","volume":"127","author":"Rosenberg","year":"1997","journal-title":"J. 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