Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
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RESEARCH
Open Access
Mitochondrial dysfunction and consequences in calpain-3-deficient muscle Vanessa E. Jahnke1, Jennifer M. Peterson2, Jack H. Van Der Meulen1, Jessica Boehler1, Kitipong Uaesoontrachoon1, Helen K. Johnston1,3, Aurelia Defour1, Aditi Phadke1, Qing Yu1, Jyoti K. Jaiswal1,3 and Kanneboyina Nagaraju1,3,4*
Abstract Background: Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive. Methods: Cell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpaired t test was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time. Results: We find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair. Conclusion: Our results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A. Keywords: LGMD2A, Mitochondria, Calpain-3 deficiency, Muscle membrane repair
* Correspondence: [email protected] 1 Center for Genetic Medicine Research, Children’s National Research Institute, Children’s National Hospital, Washington, D.C., USA 3 Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C., USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
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