title: 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.
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University Medical School, Chicago, Illinois 60612, USA. jzhou1@rush.edu
authors.forename: Jingsong
authors.initials: J
authors.lastname: Zhou
authors.forename: Jianxun
authors.initials: J
authors.lastname: Yi
authors.forename: Ronggen
authors.initials: R
authors.lastname: Fu
authors.forename: Erdong
authors.initials: E
authors.lastname: Liu
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ríos
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004195:Disease Models, Animal; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017975:Ruthenium Compounds / Q000494:pharmacology; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: C112020:Ru 360; D017975:Ruthenium Compounds; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D002118:Calcium