Causal role of aberrant skeletal muscle mitochondrial Calcium uptake in amyotrophic lateral sclerosis

The molecular mechanisms leading to mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) remain to be elucidated. This study investigated the pathophysiological impact of aberrant mitochondrial calcium uptake in skeletal muscle in the development of ALS. Mitochondrial calcium uptake was selectively reduced in skeletal muscle in hSOD1 ^G93A ALS mice using a temporally controlled doxycycline-inducible (TetOn) transgenic mouse model harboring a dominant negative form of Mitochondrial Calcium Uniporter (dnMCU). Early disturbance of mitochondrial calcium uptake was established by an accelerated rate of uptake in mitochondria isolated from hindlimb muscles from 6-week-old hSOD1 ^G93A ALS mice. Skeletal muscle-specific dnMCU expression in hSOD1 ^G93A mice from disease onset induced drastic improvement in mitochondrial structure and abundance in skeletal muscle, enhanced intrinsic muscle contractile function and preserved both motor unit number and neuromuscular junction structure and function. This study provides compelling evidence on the causative role of mitochondrial calcium uptake in skeletal muscle in ALS and its potential of being used as a therapeutic target.