title: The intracellular Ca²⁺ channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy.
abstract: The integrity of the plasma membrane is maintained through an active repair process, especially in skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca(2+) sensor proteins and Ca(2+)-dependent delivery of intracellular vesicles to the sites of injury. MCOLN1 (also known as TRPML1, ML1) is an endosomal and lysosomal Ca(2+) channel whose human mutations cause mucolipidosis IV (ML4), a neurodegenerative disease with motor disabilities. Here we report that ML1-null mice develop a primary, early-onset MD independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are expressed normally, membrane resealing was defective in ML1-null muscle fibers and also upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca(2+) release. Injury facilitated the trafficking and exocytosis of vesicles by upmodulating ML1 channel activity. In the dystrophic mdx mouse model, overexpression of ML1 decreased muscle pathology. Collectively, our data have identified an intracellular Ca(2+) channel that regulates membrane repair in skeletal muscle via Ca(2+)-dependent vesicle exocytosis.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xiping
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ali Samie
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Marlene
authors.initials: M
authors.lastname: Azar
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Wai Lok
authors.initials: WL
authors.lastname: Tsang
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Libing
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Nirakar
authors.initials: N
authors.lastname: Sahoo
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xinran
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhuo
authors.affiliation: 1] Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. [2] Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Garrity
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Center for Advancing Translational Science, National Institutes of Health, Maryland, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: 1] Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan, USA. [2] Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada [3] Program of Genetic and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada [4] Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada [5] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Dowling
authors.affiliation: Department of Cell and Molecular Physiology, Loyola University Chicago Health Sciences Division, Chicago, Illinois, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Cell and Molecular Physiology, Loyola University Chicago Health Sciences Division, Chicago, Illinois, USA.
authors.forename: Renzhi
authors.initials: R
authors.lastname: Han
authors.affiliation: 1] Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. [2] Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005089:Exocytosis; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; C512321:Mcoln1 protein, mouse; D050051:Transient Receptor Potential Channels