Abstract
ABSTRACTCentronuclear myopathy (CNM) is a congenital myopathy that is histopathologically characterized by centrally located nuclei, central aggregation of oxidative activity, and type I fiber 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 fibers to determine the effects on SERCA function. As expected with a 6- to 7-fold overexpression of phospholamban, 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: they histopathologically resembled human CNM, with centrally located nuclei, central aggregation of oxidative activity, type I fiber predominance and hypotrophy, progressive fibrosis and muscle weakness. This phenotype is associated with significant upregulation of muscle sarcolipin and dynamin 2, 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 increases in both total and monomeric PLN content compared with five healthy subjects, thereby justifying future studies with more CNM patients. Altogether, our results suggest that the commercially available PlnOE mouse phenotypically resembles human CNM and could be used as a model 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, might represent a novel therapeutic strategy to combat CNM.
Highlights
The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps catalyze the active transport of Ca2+ into the sarcoplasmic reticulum (SR) and play a crucial role in muscle relaxation and the maintenance of resting intracellular Ca2+ [Ca2+]i, which ranges from 30 to 100 nM in skeletal muscle (Tupling, 2009; Schiaffino and Reggiani, 2011)
The authors report that SERCA function was on average 53% lower in muscle biopsies from three patients with Centronuclear myopathy (CNM) compared with biopsies from five healthy individuals, whereas PLN expression seemed to be elevated in biopsies from patients with CNM compared with healthy controls
The findings suggest that studies to assess the role of PLN and SERCA dysfunction in human and animal CNM and myopathy in general might be worthwhile
Summary
The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps catalyze the active transport of Ca2+ into the sarcoplasmic reticulum (SR) and play a crucial role in muscle relaxation and the maintenance of resting intracellular Ca2+ [Ca2+]i, which ranges from 30 to 100 nM in skeletal muscle (Tupling, 2009; Schiaffino and Reggiani, 2011). PlnOE mice exhibited soleus muscle atrophy, but no other signs of myopathy were visualized under the light microscope (Song et al, 2004). We purchased these commercially available PlnOE mice and their wild-type (WT) littermates (000067-MU, FVB/N background, Mutant Mouse Regional Resource Centre, Columbia, MO) to assess SERCA function because the effect of PLN overexpression on SERCA activity and Ca2+ transport in skeletal muscle remains uncharacterized. Phospholamban (PLN) is a well-known inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps in muscle that maintain low levels of cytosolic Ca2+ and that play a crucial role in muscle contraction. Animal models that accurately recapitulate these histological abnormalities are required
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