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


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 vivo1,2. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness3,4. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca2+ sensor proteins5,6,7,8 and Ca2+-dependent delivery of intracellular vesicles to the sites of injury8,9. MCOLN1 (also known as TRPML1, ML1) is an endosomal and lysosomal Ca2+ channel whose human mutations cause mucolipidosis IV (ML4), a neurodegenerative disease with motor disabilities10,11. 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 Ca2+ 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 Ca2+ channel that regulates membrane repair in skeletal muscle via Ca2+-dependent vesicle exocytosis.

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Figure 1: ML1 KO mice develop early-onset progressive MD.
Figure 2: MD and muscle membrane damage of ML1 KO mice are not caused by neural degeneration and can be rescued by muscle expression of ML1.
Figure 3: Defective membrane repair capacity in ML1 KO muscle.
Figure 4: ML1 has an essential role in lysosomal exocytosis, membrane repair and protection of muscle damage in vivo.


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This work was supported by National Institutes of Health (NIH) grants (NS062792, MH096595 and AR060837 to H.X.; HL116546 and AR064241 to R.H.). We are grateful to S. Slaugenhaupt for the ML1 KO mice, L. Looger for the GCaMP3 construct, R. Edwards for the Vamp7-pHluorin construct, the Center for Live-Cell Imaging at the University of Michigan for the help on TIRF Imaging, and R. Hume and M. Akaaboune for comments on the manuscript. We appreciate the encouragement and helpful comments of other members of the Xu laboratory.

Author information




X.C. initiated the project; H.X., X.C., J.D. and R.H. designed the research; X.C., X.Z., Q.G., M.A.S., M.A., W.L.T., Y.Z. and L.D. performed the research; N.S., X.L., A.G.G., X.W., M.F. and L.X. contributed the new reagents; X.C., X.Z., Q.G., M.A.S., M.A., W.L.T., J.D., R.H. and H.X. analyzed the data; H.X. and X.C. wrote the paper with input from all the authors.

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Correspondence to Xiping Cheng or Haoxing Xu.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7 (PDF 6007 kb)

Supplementary Data Set

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SLO treatment induced exocytosis of ML1- and Vamp7-pHluorin-positive vesicles (related to Supplementary Fig. 6a).

Vesicle fusion with the plasma membrane was visualized using pHluorin-based TIRF imaging upon SLO (0.7 g/ml) treatment. Scale bar = 10 μm. (AVI 5560 kb)

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Cheng, X., Zhang, X., Gao, Q. et al. The intracellular Ca2+ channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy. Nat Med 20, 1187–1192 (2014).

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