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

Paradigms and Technologies


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.


Cheng, Xiping; Zhang, Xiaoli; Gao, Qiong; Ali Samie, Mohammad; Azar, Marlene; Tsang, Wai Lok; Dong, Libing; Sahoo, Nirakar; Li, Xinran; Zhuo, Yue; Garrity, Abigail G; Wang, Xiang; Ferrer-Alegre, Marc; Dowling, James; Xu, Li; Han, Renzhi; Xu, Haoxing;


  • Animals
  • Calcium Channels/ deficiency
  • Calcium Channels/ genetics
  • Calcium Channels/ metabolism
  • Cell Membrane/ metabolism
  • Exocytosis
  • Female
  • Humans
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred mdx
  • Mice, Knockout
  • Muscle Fibers, Skeletal/ metabolism
  • Muscle Fibers, Skeletal/ pathology
  • Muscular Dystrophy, Animal/ genetics
  • Muscular Dystrophy, Animal/ metabolism
  • Muscular Dystrophy, Animal/ pathology
  • Sarcolemma/ metabolism
  • Sarcolemma/ pathology
  • Transient Receptor Potential Channels/ deficiency
  • Transient Receptor Potential Channels/ genetics
  • Transient Receptor Potential Channels/ metabolism

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