PMID- 31340406 OWN - NLM STAT- MEDLINE DCOM- 20200814 LR - 20200814 IS - 1469-7793 (Electronic) IS - 0022-3751 (Linking) VI - 597 IP - 18 DP - 2019 Sep TI - Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction-induced loss of force-producing capacity. PG - 4831-4850 LID - 10.1113/JP277839 [doi] AB - KEY POINTS: Adeno-associated viral vector was used to elevate the expression of muscle specific kinase (MuSK) and rapsyn (a cytoplasmic MuSK effector protein) in the tibialis anterior muscle of wild-type and dystrophic (mdx) mice. In mdx mice, enhanced expression of either MuSK or rapsyn ameliorated the acute loss of muscle force associated with strain injury. Increases in sarcolemmal immunolabelling for utrophin and beta-dystroglycan suggest a mechanism for the protective effect of MuSK in mdx muscles. MuSK also caused subtle changes to the structure and function of the neuromuscular junction, suggesting novel roles for MuSK in muscle physiology and pathophysiology. ABSTRACT: Muscle specific kinase (MuSK) has a well-defined role in stabilizing the developing mammalian neuromuscular junction, but MuSK might also be protective in some neuromuscular diseases. In the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy, limb muscles are especially fragile. We injected the tibialis anterior muscle of 8-week-old mdx and wild-type (C57BL10) mice with adeno-associated viral vectors encoding either MuSK or rapsyn (a cytoplasmic MuSK effector protein) fused to green fluorescent protein (MuSK-GFP and rapsyn-GFP, respectively). Contralateral muscles injected with empty vector served as controls. One month later mice were anaesthetized with isoflurane and isometric force-producing capacity was recorded from the distal tendon. MuSK-GFP caused an unexpected decay in nerve-evoked tetanic force, both in wild-type and mdx muscles, without affecting contraction elicited by direct electrical stimulation of the muscle. Muscle fragility was probed by challenging muscles with a strain injury protocol consisting of a series of four strain-producing eccentric contractions in vivo. When applied to muscles of mdx mice, eccentric contraction produced an acute 27% reduction in directly evoked muscle force output, affirming the susceptibility of mdx muscles to strain injury. mdx muscles overexpressing MuSK-GFP or rapsyn-GFP exhibited significantly milder force deficits after the eccentric contraction challenge (15% and 14%, respectively). The protective effect of MuSK-GFP in muscles of mdx mice was associated with increased immunolabelling for utrophin and beta-dystroglycan in the sarcolemma. Elevating the expression of MuSK or rapsyn revealed several distinct synaptic and extrasynaptic effects, suggesting novel roles for MuSK signalling in muscle physiology and pathophysiology. CI - (c) 2019 The Authors. The Journal of Physiology (c) 2019 The Physiological Society. FAU - Trajanovska, S AU - Trajanovska S AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia. FAU - Ban, J AU - Ban J AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia. FAU - Huang, J AU - Huang J AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia. FAU - Gregorevic, P AU - Gregorevic P AD - Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia. AD - Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. AD - Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia. AD - Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. FAU - Morsch, M AU - Morsch M AUID- ORCID: 0000-0001-9484-8050 AD - Department of Biomedical Sciences, Macquarie University, Sydney, New South Wales, Australia. FAU - Allen, D G AU - Allen DG AUID- ORCID: 0000-0001-8605-1586 AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia. FAU - Phillips, W D AU - Phillips WD AUID- ORCID: 0000-0002-5405-8422 AD - Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190818 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Dystrophin) RN - 0 (Utrophin) RN - EC 2.7.10.1 (MuSK protein, mouse) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Animals MH - Disease Models, Animal MH - Dystrophin/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred mdx MH - Muscle Contraction/*physiology MH - Muscle Strength/physiology MH - Muscle, Skeletal/*metabolism/*physiology MH - Muscular Dystrophy, Duchenne/*metabolism MH - Neuromuscular Junction/metabolism MH - Receptor Protein-Tyrosine Kinases/*metabolism MH - Sarcolemma/metabolism MH - Signal Transduction/physiology MH - Utrophin/metabolism OTO - NOTNLM OT - Duchenne muscular dystrophy OT - MuSK OT - Rapsyn OT - mdx OT - muscle contraction OT - neuromuscular junction EDAT- 2019/07/25 06:00 MHDA- 2020/08/15 06:00 CRDT- 2019/07/25 06:00 PHST- 2019/02/14 00:00 [received] PHST- 2019/07/17 00:00 [accepted] PHST- 2019/07/25 06:00 [pubmed] PHST- 2020/08/15 06:00 [medline] PHST- 2019/07/25 06:00 [entrez] AID - 10.1113/JP277839 [doi] PST - ppublish SO - J Physiol. 2019 Sep;597(18):4831-4850. doi: 10.1113/JP277839. Epub 2019 Aug 18.