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Impaired chaperone activity leads to defective protein quality control that is implicated in multiple skeletal muscle diseases. The heat shock protein A4 (HSPA4) acts as a co-chaperone for HSP70. Previously, we showed that <jats:italic>Hspa4<\/jats:italic> deletion causes impaired protein homeostasis in the heart. However, its functional role in skeletal muscle has not been explored.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We performed a comparative phenotypic and biochemical analyses of <jats:italic>Hspa4<\/jats:italic> knockout (KO) mice with wild-type (WT) littermates.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>HSPA4 is markedly upregulated in regenerating WT muscle in vivo, and in differentiated myoblasts in vitro. <jats:italic>Hspa4<\/jats:italic>-KO mice are marked by growth retardation and increased variability in body weight, accompanied by 35% mortality rates during the peri-weaning period. The surviving <jats:italic>Hspa4<\/jats:italic>-KO mice experienced progressive skeletal muscle myopathy, characterized by increased number of muscle fibers with centralized nuclei, heterogeneous myofiber size distribution, inflammatory cell infiltrates and upregulation of embryonic and perinatal myosin heavy chain transcripts. <jats:italic>Hspa4<\/jats:italic>-KO muscles demonstrated an accumulation of autophagosome-associated proteins including microtubule associated protein1 light chain 3-II (LC3-II) and p62\/<jats:bold>s<\/jats:bold>equestosome accompanied by increased number of TUNEL-positive nuclei.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings underscore the indispensable role of HSPA4 in maintenance of muscle integrity through contribution in skeletal muscle autophagy and apoptosis, which might provide a novel therapeutic strategy for skeletal muscle morbidities.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-022-03418-3","type":"journal-article","created":{"date-parts":[[2022,5,14]],"date-time":"2022-05-14T13:03:34Z","timestamp":1652533414000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis"],"prefix":"10.1186","volume":"20","author":[{"given":"Manar","family":"Elkenani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal Z.","family":"Barakat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Held","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Marques","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherok","family":"Mobarak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surabhi","family":"Swarnka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim M.","family":"Adham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6705-3241","authenticated-orcid":false,"given":"Belal A.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,14]]},"reference":[{"key":"3418_CR1","doi-asserted-by":"publisher","first-page":"aac4354","DOI":"10.1126\/science.aac4354","volume":"353","author":"D Balchin","year":"2016","unstructured":"Balchin D, Hayer-Hartl M, Hartl FU. 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