SERCA function is impaired in skeletal and cardiac muscles from young DBA/2J mdx mice

Abstract

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.

Heterozygous SOD2 deletion selectively impairs SERCA function in the soleus of female mice

“…All values are mean ± SEM and are presented relative to WT. * p < 0.05 using Student's t-test (n = 5-8 per group) Schneider et al, 2013)-both of which also demonstrate increases in nitrotyrosine Cleverdon et al, 2021;Gehrig et al, 2012). Thus, SLN may be upregulated in a failing effort to protect SERCA from oxidative damage, though this requires further investigation.…”

“…Despite not observing a statistically significant increase in SLN in soleus muscles from Sod2 +/− mice, it is worth noting that SLN has been shown to play a protective role for SERCA, preventing thermal inactivation of the pump (Fu et al, 2020). Furthermore, SLN is upregulated in various models of muscle wasting including spaceflight (Braun, Geromella, et al, 2021) and muscular dystrophy (Fajardo et al, 2018; Schneider et al, 2013)—both of which also demonstrate increases in nitrotyrosine (Braun, Geromella, et al, 2021; Cleverdon et al, 2021; Gehrig et al, 2012). Thus, SLN may be upregulated in a failing effort to protect SERCA from oxidative damage, though this requires further investigation.…”