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Increased sarcolipin expression and decreased sarco(endo)plasmic reticulum Ca2+ uptake in skeletal muscles of mouse models of Duchenne muscular dystrophy

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Abstract

Abnormal intracellular Ca2+ handling is an important factor in the progressive functional decline of dystrophic muscle. In the present study, we investigated the function of sarco(endo)plasmic reticulum (SR) Ca2+ ATPase (SERCA) in various dystrophic muscles of mouse models of Duchenne muscular dystrophy. Our studies show that the protein expression of sarcolipin, a key regulator of the SERCA pump is abnormally high and correlates with decreased maximum velocity of SR Ca2+ uptake in the soleus, diaphragm and quadriceps of mild (mdx) and severe (mdx:utr−/−) dystrophic mice. These changes are more pronounced in the muscles of mdx:utr−/− mice. We also found increased expression of SERCA2a and calsequestrin specifically in the dystrophic quadriceps. Immunostaining analysis further showed that SERCA2a expression is associated both with fibers expressing slow-type myosin and regenerating fibers expressing embryonic myosin. Together, our data suggest that sarcolipin upregulation is a common secondary alteration in all dystrophic muscles and contributes to the abnormal elevation of intracellular Ca2+ concentration via SERCA inhibition.

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Acknowledgments

This work was supported by the funds from Department of Cell Biology and Molecular Medicine, UMDNJ-NJMS, Newark, NJ (to G.J.B. and D.F.). D.F. is supported by the Muscular Dystrophy Association (200037) and by the Hispanic Center of Excellence. J.S.S. is supported by a NIH training Grant (T32HL069752).

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Authors and Affiliations

  1. Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Ave, MSB, G609, Newark, NJ, 07103, USA

    Joel S. Schneider, Mayilvahanan Shanmugam, James Patrick Gonzalez, Henderson Lopez, Richard Gordan, Diego Fraidenraich & Gopal J. Babu

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  1. Joel S. Schneider
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  2. Mayilvahanan Shanmugam
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  7. Gopal J. Babu
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Correspondence to Gopal J. Babu.

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Joel S. Schneider and Mayilvahanan Shanmugam contributed equally to this study.

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Schneider, J.S., Shanmugam, M., Gonzalez, J.P. et al. Increased sarcolipin expression and decreased sarco(endo)plasmic reticulum Ca2+ uptake in skeletal muscles of mouse models of Duchenne muscular dystrophy. J Muscle Res Cell Motil 34, 349–356 (2013). https://doi.org/10.1007/s10974-013-9350-0

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