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Mechanically active tissues like skeletal muscle are particularly reliant on mechanisms to repair and remodel membrane injury, such as those caused by eccentric damage. We demonstrate that calpain-1 and -2 are master effectors of Ca<jats:sup>2+<\/jats:sup>-dependent repair of mechanical plasma membrane scrape injuries, although they are dispensable for repair\/removal of small wounds caused by pore-forming agents. Using CRISPR gene-edited human embryonic kidney 293 (HEK293) cell lines, we established that loss of both calpains-1 and -2 ( CAPNS1<jats:sup>\u2212\/\u2212<\/jats:sup>) virtually ablates Ca<jats:sup>2+<\/jats:sup>-dependent repair of mechanical scrape injuries but does not affect injury or recovery from perforation by streptolysin-O or saponin. In contrast, cells with targeted knockout of either calpain-1 ( CAPN1<jats:sup>\u2212\/\u2212<\/jats:sup>) or -2 ( CAPN2<jats:sup>\u2212\/\u2212<\/jats:sup>) show near-normal repair of mechanical injuries, inferring that both calpain-1 and calpain-2 are equally capable of conducting the cascade of proteolytic cleavage events to reseal a membrane injury, including that of the known membrane repair agent dysferlin. A severe muscular dystrophy in a murine model with skeletal muscle knockout of Capns1 highlights vital roles for calpain-1 and\/or -2 for health and viability of skeletal muscles not compensated for by calpain-3 ( CAPN3). We propose that the dystrophic phenotype relates to loss of maintenance of plasma membrane\/cytoskeletal networks by calpains-1 and -2 in response to directed and dysfunctional Ca<jats:sup>2+<\/jats:sup>-signaling, pathways hyperstimulated in the context of membrane injury. With CAPN1 variants associated with spastic paraplegia, a severe dystrophy observed with muscle-specific loss of calpain-1 and -2 activity identifies CAPN2 and CAPNS1 as plausible candidate neuromuscular disease genes. <\/jats:p>","DOI":"10.1152\/ajpcell.00408.2019","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T20:47:14Z","timestamp":1588193234000},"page":"C1226-C1237","source":"Crossref","is-referenced-by-count":16,"title":["Loss of calpains-1 and -2 prevents repair of plasma membrane scrape injuries, but not small pores, and induces a severe muscular dystrophy"],"prefix":"10.1152","volume":"318","author":[{"given":"Ann-Katrin","family":"Piper","sequence":"first","affiliation":[{"name":"Kids Neuroscience Centre, Children\u2019s Hospital at Westmead, Sydney, New South Wales, Australia"},{"name":"Discipline of Child and Adolescent Health, Faculty of Medicine, University of Sydney, Sydney, New South Wales, 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