The Role of PGC-1aplha in the Pathogenesis of Myotonic Dystrophy Type 1

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DESCRIPTION (provided by applicant): Skeletal muscle defects in myotonic dystrophy type 1 (DM1) are characterized by progressive muscle weakness and wasting, impaired mitochondrial (Mt) respiration, hyperglycemia and insulin resistance, diminished metabolic capacity and elevated oxidative stress. Highly complex and degenerative phenotypes in DM1 manifest as the result of massive expansion of a CTG tri-nucleotide repeat in the 3' translated region of DMPK gene in chromosome 19q13.3. The mechanism by which expanded CTG repeats impair Mt function and metabolic regulations in DM1 is unknown. PGC-1 is a transcription co- activator that regulates transcription of genes that regulate Mt respiration, metabolism of fatty acid and glucose and reactive oxygen species (ROS), and activity of the neuromuscular junction (NMJ). In this project our goal is to determine the extent to which diminished PGC-1 activity contributes to muscle pathogenesis in DM1: 1) aim 1 will assess expressions of PGC-1 target genes regulating Mt respiration, and function of neuromuscular junction (NMJ) in DM1 skeletal muscle. The expected outcome will establish the role of decreased PGC-1 and its target genes in skeletal muscle pathology in DM1; 2) aim 2 will establish the mechanism/s by which mutant CUG RNA disrupts intracellular redox homeostasis in DM1. These experiments will establish the mechanism by which PGC-1 target genes catalyzing metabolism of endogenous ROS are disrupted in DM1, and determine whether the activity of the ROS producing enzyme NADPH oxidase is up- regulated in DM1 myoblasts and C2C12 cells expressing mutant CUG repeats; and 3) aim 3 will explore the mechanism by which expanded CUG repeats cause a redox-dependent activation of Ataxia Telangiectasia- Mutated (ATM) kinase, phosphorylates and alters AMPK activity in DM1. We will also test whether activated AMPK modulates phosphorylation of TORC2 (transducer of regulated CREB activity), and regulates CREB activity and CREB-mediated transcription of PGC-1 in DM1. We will also test whether expanded CUG repeats modulate TORC2-mediated CREB activity and transcription of PGC-1 in DM1. The proposed study will provide insight into the mechanism by which mutant CUG RNA disrupts PGC-1 activity and impair Mt function, and might lead to the development of intervention through modulating PGC-1 signaling in DM1.