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Nat Med. 2014 Oct;20(10):1187-92. doi: 10.1038/nm.3611. Epub 2014 Sep 14.

The intracellular Ca²⁺ channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy.

Author information

1
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
2
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.
3
National Center for Advancing Translational Science, National Institutes of Health, Maryland, USA.
4
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.
5
Department of Cell and Molecular Physiology, Loyola University Chicago Health Sciences Division, Chicago, Illinois, USA.

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.

PMID:
25216637
PMCID:
PMC4192061
DOI:
10.1038/nm.3611
[Indexed for MEDLINE]
Free PMC Article

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