Centronuclear myopathy (CNM) is a congenital myopathy that is histopathologically characterized by centrally located nuclei, central aggregation of oxidative activity, and type I fibre predominance and hypotrophy. Here, we obtained commercially available mice overexpressing phospholamban (PlnOE), a well-known inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs), in their slow-twitch type I skeletal muscle fibres to determine the effects on SERCA function. As expected with a 6-7-fold overexpression of PLN, SERCA dysfunction was evident in PlnOE muscles with marked reductions in rates of Ca2+ uptake, maximal ATPase activity and the apparent affinity of SERCA for Ca2+. However, our most significant discovery was that the soleus and gluteus minimus muscles from the PlnOE mice displayed overt signs of myopathy histopathologically resembling human CNM with centrally located nuclei, central aggregation of oxidative activity, type I fibre predominance and hypotrophy, progressive fibrosis, and muscle weakness, a phenotype that is associated with significant up-regulation of muscle sarcolipin and dynamin 2 content, increased Ca2+-activated proteolysis, oxidative stress, and protein nitrosylation. Moreover, in our assessment of muscle biopsies from three human CNM patients, we found a significant 53% reduction in SERCA activity and trending increases in both total and monomeric PLN content compared to five healthy subjects, thereby justifying future studies with more CNM patients. Altogether our results suggest that the commercially available PlnOE mouse represents a novel mouse model phenotypically resembling human CNM and may be used to test potential mechanisms and therapeutic strategies. To date there is no cure for CNM and our results suggest that targeting SERCA function, which has already been shown to be an effective therapeutic target for murine muscular dystrophy and human cardiomyopathy, may represent a novel therapeutic strategy to combat CNM.
- Received March 26, 2015.
- Accepted May 21, 2015.
- © 2015. Published by The Company of Biologists Ltd
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