Calcium and the damage pathways in muscular dystrophy

• Published in: Canadian journal of physiology and pharmacology Vol. 88; no. 2; pp. 83 - 91
• Main Authors: ALLEN, David G, GERVASIO, Othon L, YEUNG, Ella W, WHITEHEAD, Nicholas P
• Format: Conference Proceeding Journal Article
• Language: English
• Published: Plattsburgh, NY National Research Council of Canada 01.02.2010; NRC Research Press; Canadian Science Publishing NRC Research Press
• Subjects: Active oxygen; Animals; Biological and medical sciences; Calcium; Calcium - chemistry; Calcium - metabolism; Calcium - physiology; Calcium channels; Calcium Signaling - physiology; Duchenne muscular dystrophy; Dystrophin; Fundamental and applied biological sciences. Psychology; Genetic aspects; Health aspects; Humans; Mice; Mice, Inbred mdx; Muscular dystrophy; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - pathology; Muscular system; Myoblasts - cytology; Myoblasts - metabolism; Myoblasts - physiology; Physiological aspects; Risk factors; Signal Transduction - physiology; TRPC Cation Channels - chemistry; TRPC Cation Channels - physiology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Hong Kong; Australia; Nervous system diseases; Neuromuscular diseases; Vertebrata; Mammalia; Calcium; Mouse; Rodentia; Intracellular; Inorganic element; Dystrophin; Muscular dystrophy; Genetic disease
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/Y09-058

Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease caused by the absence of the cytoskeletal protein dystrophin. Experiments on the mdx mouse, a model of DMD, have shown that mdx muscles are particularly susceptible to stretch-induced damage. In this review, we discuss evidence showing that a series of stretched contractions of mdx muscle fibres causes a prolonged increase in resting intracellular calcium concentration ([Ca2+]i). The rise in [Ca2+]i is caused by Ca2+ entry through a class of stretch-activated channels (SACNSC) for which one candidate gene is TRPC1. We review the evidence for activation of SACNSC in muscle by reactive oxygen species (ROS) and suggest that stretch-induced ROS production is part of the pathway that triggers increased channel activity. When the TRPC1 gene was transfected into C2 myoblasts, expression occurred throughout the cell. Only when the TRPC1 gene was coexpressed with caveolin-3 did the TRPC1 protein express in the membrane. When TRPC1 was expressed in the membrane, it could be activated by ROS to produce Ca2+ entry and this entry was inhibited by PP2, an inhibitor of src kinase. These results suggest that stretched contractions activate ROS production, which activates src kinase. Activity of this kinase causes opening of SACNSC and allows Ca2+ entry. This pathway appears to be a significant cause of muscle damage in DMD.