Investigating Exercise as an Approach to Remodeling Motor Unit Fibre Type in Amyotrophic Lateral Sclerosis (P7.192)

OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition, characterized by the preferential destruction of motor neurons innervating fast-twitch muscle. The goal of this study is to promote skeletal muscle fiber type conversion from fast to slow phenotype using exercise. We hypothesise that this conversion would delay neurodegeneration in the G93A human SOD1 transgenic mouse model of ALS. BACKGROUND: Is exercise neuroprotective, or does high-intensity activity influence ALS development? This is an ongoing debate in the ALS literature. Due to degeneration of fast-twitch muscle motor units, conversion of motor units to a slow-oxidative phenotype should promote neuroprotection in ALS. Muscle regulatory factors, myogenin and MyoD have been used to alter muscle fiber type composition in mice; myogenin gene transfer increases oxidative phenotype, whereas MyoD gene transfer reduces oxidative phenotype and hastens disease process. This study aims to demonstrate a relationship between exercise and altered muscle expression of myogenin and MyoD. DESIGN/METHODS: Transgenic mice overexpressing the G93A human SOD1 mutation (n=9) and wild type controls (n=6) were randomized into exercise and sedentary groups. Mice engaged in a treadmill-based interval program or remained sedentary three days weekly for eight weeks. Mice were weighed weekly. Spinal cord and muscle samples were collected and frozen following the intervention; half were used for mRNA extraction and cDNA generation for qPCR analysis using standard techniques. RESULTS: Mice showed improvement on the running task over the study duration. Real-time quantitative polymerase chain reaction (PCR) of muscle regulatory factors (myogenin and MyoD), myosin heavy-chain type (Myh7, Myh2, Myh4), and IGF-1 will be completed on hindlimb and spinal cord samples. A succinate dehydrogenase enzyme assay will be performed to assess muscle oxidative capacity. CONCLUSIONS: These results will inform efforts to develop specific muscle-directed exercise therapies for motor neuron diseases. Study Supported by: AAN Student Research Scholarship, UBC, and CMMT Disclosure: Dr. Plecash has nothing to disclose. Dr. Lu has nothing to disclose. Dr. Hill has nothing to disclose. Dr. Leavitt has nothing to disclose.