SERCA-mediated calcium uptake in the DBA/2J vs C57BL/10 mdx models of Duchenne muscular dystrophy

The C57BL/10ScSn-Dmdmdx/J (C57 mdx) mouse is the most commonly used murine model of Duchenne muscular dystrophy (DMD) but displays a mild phenotype with a late onset, greatly limiting translatability to clinical research. In consequence, the D2.B10-Dmdmdx/J (D2 mdx) mouse was created and produces a more severe, early onset phenotype. Mechanistic insights of the D2 mdx phenotype have yet to be elucidated, specifically related to sarcoplasmic reticulum (SR) calcium (Ca2+) handling. In our study, we aimed to determine if SR Ca2+ handling differences in the D2 mdx versus the C57 mdx mouse could explain model phenotypes. Firstly, analyses determined that D2 mdx mice ambulate less and have weaker muscles, but have greater energy expenditure than C57 counterparts. SR Ca2+ handling measures determined that only D2 mdx mice have impaired SR calcium intake in the gastrocnemius, left ventricle and diaphragm. This was coupled with decrements in maximal sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity and greater activation of the Ca2+-activated protease, calpain, in the gastrocnemius. Overall, our study is the first to determine that SR Ca2+ handling is impaired in the D2 mdx mouse, specifically at the level of the SERCA pump.