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Genetic loss of dysferlin results in limb girdle muscular dystrophy 2B\/2R (LGMD2B\/2R) and other dysferlinopathies \u2013 rare untreatable muscle diseases that lead to permanent loss of ambulation in humans. The mild disease severity in dysferlin\u2010deficient mice and diverse genotype\u2010phenotype relationships in LGMD2B patients have prompted the development of new in vitro models for personalized studies of dysferlinopathy. Here the first 3\u2010D tissue\u2010engineered hiPSC\u2010derived skeletal muscle (\u201cmyobundle\u201d) model of LGMD2B is described that exhibits compromised contractile function, calcium\u2010handling, and membrane repair, and transcriptomic changes indicative of impaired oxidative metabolism and mitochondrial dysfunction. In response to the fatty acid (FA) challenge, LGMD2B myobundles display mitochondrial deficits and intracellular lipid droplet (LD) accumulation. Treatment with the ryanodine receptor (RyR) inhibitor dantrolene or the dissociative glucocorticoid vamorolone restores LGMD2B contractility, improves membrane repair, and reduces LD accumulation. Lastly, it is demonstrated that chemically induced chronic RyR leak in healthy myobundles phenocopies LGMD2B contractile and metabolic deficit, but not the loss of membrane repair capacity. Together, these results implicate intramyocellular Ca<jats:sup>2+<\/jats:sup> leak as a critical driver of dysferlinopathic phenotype and validate the myobundle system as a platform to study LGMD2B pathogenesis.<\/jats:p>","DOI":"10.1002\/advs.202400188","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T01:50:28Z","timestamp":1718675428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-7083","authenticated-orcid":false,"given":"Alastair","family":"Khodabukus","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham NC 27708 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