Hyperactive Intracellular Calcium Signaling Associated with Localized Mitochondrial Defects in Skeletal Muscle of an Animal Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by degeneration of motor neurons and atrophy of skeletal muscle. Mutations in the superoxide dismutase (SOD1) gene are linked to 20% cases of inherited ALS. Mitochondrial dysfunction has been implicated in the pathogenic process, but how it contributes to muscle degeneration of ALS is not known. Here we identify a specific deficit in the cellular physiology of skeletal muscle derived from an ALS mouse model (G93A) with transgenic overexpression of the human SOD1 G93A mutant. The G93A skeletal muscle fibers display localized loss of mitochondrial inner membrane potential in fiber segments near the neuromuscular junction. These defects occur in young G93A mice prior to disease onset. Fiber segments with depolarized mitochondria show greater osmotic stress-induced Ca 2؉ release activity, which can include propagating Ca 2؉ waves. These Ca 2؉ waves are confined to regions of depolarized mitochondria and stop propagating shortly upon entering the regions of normal, polarized mitochondria. Uncoupling of mitochondrial membrane potential with FCCP or inhibition of mitochondrial Ca 2؉ uptake by Ru360 lead to cell-wide propagation of such Ca 2؉ release events. Our data reveal that mitochondria regulate Ca 2؉ signaling in skeletal muscle, and loss of this capacity may contribute to the progression of muscle atrophy in ALS.

Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle – pivotal roles in Ca2+ and reactive oxygen species signaling

“…In another knock-in mouse model of MH, RyR1(R163C), bioenergetics defects, including elevated [Ca 2+ ] m and ROS, and decreased oxidative phosphorylation have been reported (Giulivi et al, 2011). These results imply that there is a Zhou et al, 2010;Yi et al, 2011) Duchenne muscular dystrophy (dystrophin mutations) Robert et al, 2001a;Shkryl et al, 2009;Bellinger et al, 2009;Millay et al, 2008;Goonasekera et al, 2011 (Chang et al, 2012) Smooth muscle atrophy (CSQ-1 knockout) (Paolini et al, 2007) Aging and/or sarcopenia (RyR1, b-amyloid) Boncompagni et al, 2012) n.d., not determined.…”

“…In skeletal muscle fibers derived from the SOD1(G93A) knock-in mouse model, depolarized mitochondria have been found in the area surrounding the neuromuscular junction (Zhou et al, 2010). Osmotic stress triggers Ca 2+ release waves that are confined to the area of depolarized mitochondria.…”

“…Osmotic stress triggers Ca 2+ release waves that are confined to the area of depolarized mitochondria. However, Ca 2+ waves propagate throughout the muscle fibers upon inhibition of mitochondrial Ca 2+ uptake by an uncoupler or Ru360 (Zhou et al, 2010). Furthermore, in the regions of depolarized mitochondria, [Ca 2+ ] c signals that are associated with depolarization-induced excitation-contraction (EC) coupling are increased, whereas the amplitude of the [Ca 2+ ] m transients is decreased (Yi et al, 2011).…”

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

“…Mice with conditional postnatal ablation of tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight (TDP-43) develop rapid weight loss and increased fatty acid oxidation, and experience early death . At the cellular level, mitochondria from spinal cord and muscle of mSOD1 and TDP-43 mice possess both morphological and physiological abnormalities (Bendotti et al, 2001;Mattiazzi et al, 2002;Cassina et al, 2008;Pedrini et al, 2010;Shan et al, 2010;Xu et al, 2010;Zhou et al, 2010;Braun et al, 2011). Compromised mitochondrial function may contribute to systemic metabolic defects in the organismal level.…”

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

“…Eph and Lar-related receptors are expressed in motor neurons and striated muscles. While both cell types are implicated in ALS, their respective roles are not well delineated (Dupuis et al, 2011;Turner et al, 2013;Zhou et al, 2010). Familial ALS patients carry the pathogenic mutation throughout their lives.…”