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Published on: September 20, 2019
Poloxamer 188 reduces the contraction-induced force decline in lumbrical muscles from mdx mice
Rainer Ng1, Joseph M Metzger, Dennis R Claflin
1Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109-2200, USA.
Abstract:
Duchenne Muscular Dystrophy is a genetic disease caused by the lack of the protein dystrophin. Dystrophic muscles are highly susceptible to contraction-induced injury, and following contractile activity, have disrupted plasma membranes that allow leakage of calcium ions into muscle fibers. Because of the direct relationship between increased intracellular calcium concentration and muscle dysfunction, therapeutic outcomes may be achieved through the identification and restriction of calcium influx pathways. Our purpose was to determine the contribution of sarcolemmal lesions to the force deficits caused by contraction-induced injury in dystrophic skeletal muscles. Using isolated lumbrical muscles from dystrophic (mdx) mice, we demonstrate for the first time that poloxamer 188 (P188), a membrane-sealing poloxamer, is effective in reducing the force deficit in a whole mdx skeletal muscle. A reduction in force deficit was also observed in mdx muscles that were exposed to a calcium-free environment. These results, coupled with previous observations of calcium entry into mdx muscle fibers during a similar contraction protocol, support the interpretation that extracellular calcium enters through sarcolemmal lesions and contributes to the force deficit observed in mdx muscles. The results provide a basis for potential therapeutic strategies directed at membrane stabilization of dystrophin-deficient skeletal muscle fibers.
Insights
Duchenne muscular dystrophy (DMD) muscles show force deficits after contraction due to membrane damage and calcium leakage. Membrane sealant poloxamer 188 (P188) and calcium restriction reduce these deficits, suggesting therapeutic potential.
Area of Science:
- Muscle Physiology
- Cellular Biology
- Biomedical Research
Background:
- Duchenne muscular dystrophy (DMD) results from dystrophin deficiency, leading to muscle membrane fragility.
- Contraction-induced injury in dystrophic muscles causes plasma membrane disruption and calcium ion influx.
- Elevated intracellular calcium correlates with muscle dysfunction, highlighting calcium pathways as therapeutic targets.
Purpose of the Study:
- To investigate the role of sarcolemmal lesions in contraction-induced force deficits in dystrophic skeletal muscles.
- To evaluate the efficacy of poloxamer 188 (P188) in mitigating these force deficits.
Main Methods:
- Isolated lumbrical muscles from dystrophin-deficient (mdx) mice were used.
- Muscles were subjected to contraction protocols.
- Effects of poloxamer 188 (P188) and a calcium-free environment on force deficits were assessed.
Main Results:
- Poloxamer 188 (P188) significantly reduced the force deficit in mdx skeletal muscles.
- Exposure to a calcium-free environment also led to a reduction in force deficit.
- Results support calcium influx through sarcolemmal lesions as a contributor to force loss.
Conclusions:
- Extracellular calcium entry via sarcolemmal lesions contributes to force deficits in dystrophin-deficient muscles.
- Membrane stabilization strategies, such as using P188, show therapeutic promise for DMD.
- Targeting membrane integrity offers a potential therapeutic avenue for dystrophinopathies.
