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dc.contributor.authorMichailowsky, V.
dc.contributor.authorLi, H.
dc.contributor.authorMittra, B.
dc.date.accessioned2019-03-29T14:47:34Z
dc.date.available2019-03-29T14:47:34Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85059503390&doi=10.1186%2fs13395-018-0187-5&partnerID=40&md5=13c10d547cddc620c9c445b3407cb5c1
dc.identifier.urihttp://hdl.handle.net/10713/8658
dc.description.abstractBackground: Niemann-Pick disease type A (NPDA), a disease caused by mutations in acid sphingomyelinase (ASM), involves severe neurodegeneration and early death. Intracellular lipid accumulation and plasma membrane alterations are implicated in the pathology. ASM is also linked to the mechanism of plasma membrane repair, so we investigated the impact of ASM deficiency in skeletal muscle, a tissue that undergoes frequent cycles of injury and repair in vivo. Methods: Utilizing the NPDA/B mouse model ASM -/- and wild type (WT) littermates, we performed excitation-contraction coupling/Ca 2+ mobilization and sarcolemma injury/repair assays with isolated flexor digitorum brevis fibers, proteomic analyses with quadriceps femoris, flexor digitorum brevis, and tibialis posterior muscle and in vivo tests of the contractile force (maximal isometric torque) of the quadriceps femoris muscle before and after eccentric contraction-induced muscle injury. Results: ASM -/- flexor digitorum brevis fibers showed impaired excitation-contraction coupling compared to WT, a defect expressed as reduced tetanic [Ca 2+ ] i in response to electrical stimulation and early failure in sustaining [Ca 2+ ] i during repeated tetanic contractions. When injured mechanically by needle passage, ASM -/- flexor digitorum brevis fibers showed susceptibility to injury similar to WT, but a reduced ability to reseal the sarcolemma. Proteomic analyses revealed changes in a small group of skeletal muscle proteins as a consequence of ASM deficiency, with downregulation of calsequestrin occurring in the three different muscles analyzed. In vivo, the loss in maximal isometric torque of WT quadriceps femoris was similar immediately after and 2 min after injury. The loss in ASM -/- mice immediately after injury was similar to WT, but was markedly larger at 2 min after injury. Conclusions: Skeletal muscle fibers from ASM -/- mice have an impairment in intracellular Ca 2+ handling that results in reduced Ca 2+ mobilization and a more rapid decline in peak Ca 2+ transients during repeated contraction-relaxation cycles. Isolated fibers show reduced ability to repair damage to the sarcolemma, and this is associated with an exaggerated deficit in force during recovery from an in vivo eccentric contraction-induced muscle injury. Our findings uncover the possibility that skeletal muscle functional defects may play a role in the pathology of NPDA/B disease. © 2019 The Author(s).en_US
dc.description.sponsorshipResearch reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R21AR071011 (N.W.A.), and National Institutes of Health training grants T32 AR-007592 (S.I.) and T32AR056993 (D.A.G.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.en_US
dc.description.urihttps://dx.doi.org/10.1186/s13395-018-0187-5en_US
dc.language.isoen_USen_US
dc.publisherBioMed Central Ltd.en_US
dc.relation.ispartofSkeletal Muscle
dc.subjectAcid sphingomyelinaseen_US
dc.subjectCalciumen_US
dc.subjectLysosomeen_US
dc.subjectPlasma membrane repairen_US
dc.subjectSkeletal muscleen_US
dc.titleDefects in sarcolemma repair and skeletal muscle function after injury in a mouse model of Niemann-Pick type A/B diseaseen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s13395-018-0187-5
dc.identifier.pmid30611303


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