Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is typically fatal within 3–5 years of diagnosis. While motoneuron death is the defining characteristic of ALS, the events that underlie its pathology are not restricted to the nervous system. In this regard, ALS muscle atrophies and weakens significantly before presentation of neurological symptoms. Since the skeletal muscle L-type Ca2+ channel (CaV1.1) is a key regulator of both mass and force, we investigated whether CaV1.1 function is impaired in the muscle of two distinct mouse models carrying an ALS-linked mutation.MethodsWe recorded L-type currents, charge movements, and myoplasmic Ca2+ transients from dissociated flexor digitorum brevis (FDB) fibers to assess CaV1.1 function in two mouse models expressing a type 1 Cu/Zn superoxide dismutase mutant (SOD1G93A).ResultsIn FDB fibers obtained from “symptomatic” global SOD1G93A mice, we observed a substantial reduction of SR Ca2+ release in response to depolarization relative to fibers harvested from age-matched control mice. L-type current and charge movement were both reduced by ~40 % in symptomatic SOD1G93A fibers when compared to control fibers. Ca2+ transients were not significantly reduced in similar experiments performed with FDB fibers obtained from “early-symptomatic” SOD1G93A mice, but L-type current and charge movement were decreased (~30 and ~20 %, respectively). Reductions in SR Ca2+ release (~35 %), L-type current (~20 %), and charge movement (~15 %) were also observed in fibers obtained from another model where SOD1G93A expression was restricted to skeletal muscle.ConclusionsWe report reductions in EC coupling, L-type current density, and charge movement in FDB fibers obtained from symptomatic global SOD1G93A mice. Experiments performed with FDB fibers obtained from early-symptomatic SOD1G93A and skeletal muscle autonomous MLC/SOD1G93A mice support the idea that events occurring locally in the skeletal muscle contribute to the impairment of CaV1.1 function in ALS muscle independently of innervation status.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0094-6) contains supplementary material, which is available to authorized users.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is typically fatal within 3–5 years of diagnosis
EC coupling is impaired in symptomatic SOD1G93A flexor digitorum brevis (FDB) fibers Like humans afflicted with ALS, mice engineered to carry ALS-linked mutations in Cu/Zn superoxide dismutase 1 (SOD1) display substantial muscle atrophy and decreased specific force [30, 32]
We dialyzed flexor digitorum brevis (FDB) fibers isolated from congenic SOD1G93A mice and age-matched C57BL/6J wild-type control mice with cell-impermeant Fluo 3 Ca2+ indicator dye and recorded depolarization-induced myoplasmic Ca2+ transients in the whole-cell configuration
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is typically fatal within 3–5 years of diagnosis. A quarter of familial ALS cases have been linked to point mutations in the type 1 Cu/Zn superoxide dismutase (SOD1) enzyme, which functions to mitigate cellular oxidative stress [3]. Two independent groups have found that skeletal muscle-targeted, transgenic overexpression of SOD1G93A causes profound muscle atrophy [6, 7] and initiates motoneuron death [7] These congruent reports reinforce earlier challenges to the dogma that ALS is solely a neurological disorder and support the “dying-back” phenomenon by which motor unit loss and associated muscle function precede the death of motor neurons Additional support for this view is provided by the observations that destruction of neuromuscular junctions has been linked to oxidative stress induced by tissue-specific breakdown of muscle mitochondria [12] and trophic factors secreted from the skeletal muscle promote motoneuron survival in an ALS model by stabilizing neuromuscular junctions (e.g., IGF-1, GDNF) [13,14,15]
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