Progressive impairment of Ca _V1.1 function in the skeletal muscle of mice expressing a mutant type 1 Cu/Zn superoxide dismutase (G93A) linked to amyotrophic lateral sclerosis

Abstract

Background

Amyotrophic 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 Ca ²⁺ channel (Ca _V1.1) is a key regulator of both mass and force, we investigated whether Ca _V1.1 function is impaired in the muscle of two distinct mouse models carrying an ALS-linked mutation.

Methods

We recorded L-type currents, charge movements, and myoplasmic Ca ²⁺ transients from dissociated flexor digitorum brevis (FDB) fibers to assess Ca _V1.1 function in two mouse models expressing a type 1 Cu/Zn superoxide dismutase mutant (SOD1 ^G93A).

Results

In FDB fibers obtained from “symptomatic” global SOD1 ^G93A mice, we observed a substantial reduction of SR Ca ²⁺ 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 SOD1 ^G93A fibers when compared to control fibers. Ca ²⁺ transients were not significantly reduced in similar experiments performed with FDB fibers obtained from “early-symptomatic” SOD1 ^G93A mice, but L-type current and charge movement were decreased (~30 and ~20 %, respectively). Reductions in SR Ca ²⁺ release (~35 %), L-type current (~20 %), and charge movement (~15 %) were also observed in fibers obtained from another model where SOD1 ^G93A expression was restricted to skeletal muscle.

Conclusions

We report reductions in EC coupling, L-type current density, and charge movement in FDB fibers obtained from symptomatic global SOD1 ^G93A mice. Experiments performed with FDB fibers obtained from early-symptomatic SOD1 ^G93A and skeletal muscle autonomous MLC/SOD1 ^G93A mice support the idea that events occurring locally in the skeletal muscle contribute to the impairment of Ca _V1.1 function in ALS muscle independently of innervation status.

Electronic supplementary material

The online version of this article (doi:10.1186/s13395-016-0094-6) contains supplementary material, which is available to authorized users.