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Reduced Sarcolemmal Membrane Repair Exacerbates Striated Muscle Pathology in a Mouse Model of Duchenne Muscular
Brian J Paleo1, Kevin E McElhanon1, Hannah R Bulgart1
1Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Abstract:
Duchenne muscular dystrophy (DMD) is a common X-linked degenerative muscle disorder that involves mutations in the DMD gene that frequently reduce the expression of the dystrophin protein, compromising the structural integrity of the sarcolemmal membrane and leaving it vulnerable to injury during cycles of muscle contraction and relaxation. This results in an increased frequency of sarcolemma disruptions that can compromise the barrier function of the membrane and lead to death of the myocyte. Sarcolemmal membrane repair processes can potentially compensate for increased membrane disruptions in DMD myocytes. Previous studies demonstrated that TRIM72, a muscle-enriched tripartite motif (TRIM) family protein also known as mitsugumin 53 (MG53), is a component of the cell membrane repair machinery in striated muscle. To test the importance of membrane repair in striated muscle in compensating for the membrane fragility in DMD, we crossed TRIM72/MG53 knockout mice into the mdx mouse model of DMD. These double knockout (DKO) mice showed compromised sarcolemmal membrane integrity compared to mdx mice, as measured by immunoglobulin G staining and ex vivo muscle laser microscopy wounding assays. We also found a significant decrease in muscle ex vivo contractile function as compared to mdx mice at both 6 weeks and 1.5 years of age. As the DKO mice aged, they developed more extensive fibrosis in skeletal muscles compared to mdx. Our findings indicate that TRIM72/MG53-mediated membrane repair can partially compensate for the sarcolemmal fragility associated with DMD and that the loss of membrane repair results in increased pathology in the DKO mice.
Insights
Duchenne muscular dystrophy (DMD) involves muscle membrane fragility. The protein TRIM72/MG53 aids membrane repair, partially compensating for DMD-related damage and reducing pathology.
Area of Science:
- Muscle physiology and disease
- Cell membrane biology
- Genetic disorders
Background:
- Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by DMD gene mutations, leading to reduced dystrophin protein.
- This deficiency compromises sarcolemmal membrane integrity, increasing vulnerability to injury during muscle activity.
- Cell membrane repair mechanisms, including TRIM72/MG53, are crucial for maintaining muscle health.
Purpose of the Study:
- To investigate the role of TRIM72/MG53-mediated membrane repair in compensating for sarcolemmal fragility in DMD.
- To assess the impact of impaired membrane repair on DMD pathology using a mouse model.
Main Methods:
- Generated double knockout (DKO) mice by crossing TRIM72/MG53 knockout mice with the mdx mouse model of DMD.
- Assessed sarcolemmal membrane integrity using immunoglobulin G staining and ex vivo laser microscopy wounding assays.
- Evaluated ex vivo muscle contractile function and analyzed skeletal muscle fibrosis development with aging.
Main Results:
- DKO mice exhibited compromised sarcolemmal membrane integrity compared to mdx mice.
- Significant decreases in ex vivo muscle contractile function were observed in DKO mice at multiple ages.
- Aging DKO mice developed more extensive skeletal muscle fibrosis than mdx mice.
Conclusions:
- TRIM72/MG53-mediated membrane repair partially compensates for sarcolemmal fragility in Duchenne muscular dystrophy.
- Loss of TRIM72/MG53 function exacerbates DMD pathology, including membrane instability and functional decline.
- These findings highlight the critical role of sarcolemmal repair in mitigating DMD progression.
