SERCA1 overexpression in skeletal muscle preserves motor function and delays disease onset in a mouse model of ALS

Abstract

We previously showed that disruption of intracellular Ca2+ homeostasis in skeletal muscle is one of the pathophysiological features of amyotrophic lateral sclerosis (ALS). The purpose of this study was to investigate whether SERCA1 overexpression would improve motor function and disease progression in ALS mice. B6SJL‐Tg(SOD1*G93A)1Gur/J (ALS) mice were bred with skeletal muscle α‐actinin SERCA1 overexpressing mice to generate: i) wild type (WT; n=11); ii) SERCA1 overexpression (WT/+SERCA1; n=14); iii) SOD1*G93A ALS (ALS; n=7); iv) SERCA1 overexpressing SOD1*G93A ALS mice (ALS/+SERCA1; n=11). Mice were evaluated weekly (9 ‐16 wks) for motor function (grip test) and time of symptom onset and at 16 wks for muscle mass and SERCA1 activity. SERCA1 overexpressing mice had decreased gastrocnemius muscle mass in WT (125.4 ± 5.9 vs. 71.9 ± 13.1 mg; p<0.05 for WT vs. WT/+SERCA1) but increased mass in ALS (59.6 ± 0.1 vs. 73.1 ± 0.1 mg; p<0.05 for ALS vs. ALS/+SERCA1). SERCA1 overexpression resulted in a 1.8‐fold increase in SR Ca2+ ATPase activity in ALS mice (39.9 ± 2.1 vs. 70.4 ± 12.4 umol/g tissue mass/min; p<0.05 for ALS vs. ALS/+SERCA1). This was associated with improved motor function in ALS mice at 14 wks (111.4 ± 16.2 vs. 67.7 ± 13.1 sec; p<0.05) and 16 wks (53.1 ± 11.8 vs. 8.9 ± 3.4 sec; p<0.05) for ALS/+SERCA1 vs. ALS mice and a delay in disease onset (101.9 ± 2.6 vs. 91.1 ± 4.7 days in ALS/+SERCA1 vs. ALS). These data indicate that SERCA1 overexpression in skeletal muscle improves motor function and slows disease progression in a mouse model of ALS. We hypothesize that this is due to improved muscle health and stability of the neuromuscular junction. Increasing SERCA1 expression and/or activity in skeletal muscle may be a new therapeutic strategy to treat ALS.