Ca Signaling in Progression of Amyotrophic Lateral Sclerosis in Skeletal Muscle

Rush University Medical Center, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder involving degeneration of motor neurons and atrophy of skeletal muscle. Mutations in the superoxide dismutase (SOD1) gene are linked to most cases of inherited ALS, resulting in impaired metabolic function of the mitochondria. Currently, there is a lack of knowledge on how dysfunctional mitochondria and altered Ca signaling contribute to muscle degeneration during ALS progression. This new investigator initiated research project will test the hypothesis that during the development of ALS, action potential activity at the neuromuscular junction (NMJ) will cause local Ca overload in mitochondria compromised by the presence of mutant SOD1. This overload will further disrupt mitochondria-sarcoplasmic reticulum (SR) coupling and lead to altered Ca and reactive oxygen species (ROS) signaling. The alteration in turn will increase local Ca, reinforcing the local deficit, thus constituting a primary event in the pathophysiology of ALS muscle. The central theme of our studies is to develop a comprehensive understanding of the cellular mechanism that contributes to the progressive decline in mitochondria-SR coupling leading to the compromised Ca homeostatic capacity of ALS muscle. We anticipate that information obtained from our research will apply to other neuromuscular diseases, such as aging, diabetes, Parkinson's disease and others, where altered Ca signaling and intracellular oxidative stress are linked to dysfunctional muscle contractility and altered motor neuron communication. In Aim 1, we propose to quantify the mitochondrial contribution to local control of SR Ca signaling, and use this quantification to evaluate how defective mitochondria-SR coupling contributes to progression of muscle wasting in ALS. By characterizing the changes in Ca signaling and mitochondrial function in skeletal muscle at different stages of ALS progression, our studies should provide a mechanistic understanding of how local control of SR Ca signaling is altered by mitochondria, how this process is altered in ALS muscle and what is the influence of axonal withdrawal in disrupting SR-mitochondria coupling leading to the progressive decline of muscle function in ALS. In Aim 2, we propose to use localized mitochondrial superoxide (O2-) FLASH signal as an index for mitochondrial metabolic function in ALS muscle, and to examine the effect of denervation on the interplay between mitochondria-SR in controlling intracellular Ca release and local O2- levels during the progression of muscle atrophy in ALS. These studies will reveal the role of localized coupling between Ca and O2- production in muscle physiology, and establish the cellular mechanism(s) that contribute to NMJ remodeling and the progressive development of muscle pathology in ALS.