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

• Published in: The Journal of biological chemistry Vol. 285; no. 1; pp. 705 - 712
• Main Authors: Zhou, Jingsong, Yi, Jianxun, Fu, Ronggen, Liu, Erdong, Siddique, Teepu, Ríos, Eduardo, Deng, Han-Xiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2010; American Society for Biochemistry and Molecular Biology
• Subjects: Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Calcium - metabolism; Calcium Signaling - drug effects; Calcium/Imaging; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone - pharmacology; Disease Models, Animal; Intracellular Ca2+ Release; Intracellular Space - drug effects; Intracellular Space - metabolism; Mechanisms of Signal Transduction; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondria - drug effects; Mitochondria - pathology; Mitochondria - ultrastructure; Mitochondrial Ca2+ Uptake; Models, Biological; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle Fibers, Skeletal - ultrastructure; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - ultrastructure; Neuromuscular Junction; Neuromuscular Junction - drug effects; Neuromuscular Junction - metabolism; Neuromuscular Junction - pathology; Neuromuscular Junction - ultrastructure; Ruthenium Compounds - pharmacology; Skeletal Muscle; Stress, Physiological - drug effects; Superoxide Dismutase; Calcium/Imaging; Amyotrophic Lateral Sclerosis; Skeletal Muscle; Neuromuscular Junction; Intracellular Ca2+ Release; Mitochondrial Ca2+ Uptake; Superoxide Dismutase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.041319

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 SOD1G93A 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 Ca2+ release activity, which can include propagating Ca2+ waves. These Ca2+ 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 Ca2+ uptake by Ru360 lead to cell-wide propagation of such Ca2+ release events. Our data reveal that mitochondria regulate Ca2+ signaling in skeletal muscle, and loss of this capacity may contribute to the progression of muscle atrophy in ALS.