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Increased calcium influx in dystrophic muscle
P R Turner1, P Y Fong, W F Denetclaw
1Department of Molecular and Cell Biology, University of California, Berkeley 94720.
The Journal of Cell Biology
|December 1, 1991
Summary
Elevated intracellular calcium in muscular dystrophy is linked to increased calcium leak channel activity. This heightened influx, not altered calcium handling, contributes to muscle fiber dysfunction in Duchenne muscular dystrophy.
Area of Science:
- Biochemistry
- Cell Biology
- Muscle Physiology
Background:
- Duchenne muscular dystrophy (DMD) is characterized by elevated intracellular calcium levels ([Ca2+]i) in muscle fibers.
- The precise mechanisms driving this calcium dysregulation in dystrophic muscle remain incompletely understood.
Purpose of the Study:
- To investigate the pathways responsible for elevated resting [Ca2+]i in dystrophic mouse (mdx) and human Duchenne muscular dystrophy myotubes.
- To determine if altered calcium influx or efflux contributes to the observed [Ca2+]i elevation.
Main Methods:
- Utilized the calcium indicator fura-2 to measure [Ca2+]i in mdx and normal muscle fibers and myotubes.
- Assessed calcium transient decay times and resting free sodium levels using sodium-binding benzofuran isophthalate.
- Investigated the role of calcium leak channels by examining their opening probabilities (Po) and the effects of modulating their activity.
Main Results:
- Dystrophic (mdx) fibers exhibited impaired regulation of [Ca2+]i near the sarcolemma.
- Calcium transient decay was similar in normal and mdx fibers when resting [Ca2+]i was normalized, indicating intact calcium sequestration but slowed by elevated resting levels.
- Resting free sodium levels and influx rates were comparable between normal and dystrophic cells, suggesting a calcium-specific defect.
- Calcium leak channels, with voltage-independent opening, were identified as a potential major pathway for resting calcium influx.
- Increased leak channel activity correlated with elevated [Ca2+]i in dystrophic muscle fibers and myotubes.
Conclusions:
- The elevated resting [Ca2+]i in dystrophic muscle is primarily due to increased calcium influx through calcium leak channels.
- This increased influx, rather than impaired calcium sequestration, is a key factor in the pathophysiology of Duchenne muscular dystrophy.
- Calcium leak channels represent a potential therapeutic target for managing calcium dysregulation in muscular dystrophy.