City of Hope (COH)

Role of a Novel Inc-RNA-MicroRNA Axis in Promoting Skeletal Muscle Atrophy/Wasting

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Skeletal muscle plays a key role in metabolic control and blood glucose management. However, muscle loss is common in Type1diabetic (T1D) patients, which decreases their quality of life and increases risk of complications and early death. The goal of my project is to identify novel factors that lead to T1D-associated muscle loss (or wasting) and develop new humanized mouse models to determine the potential of targeting these factors to treat skeletal muscle atrophy inT1Dpatients. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are RNA molecules that regulate expression of genes or proteins involved in biological processes. Our data shows that a key microRNA can lead to loss of muscle mass in T1DandT1D mice lacking this microRNA had significant protection against this loss. T1D exacerbates muscle dysfunction by promoting damage to the energy generating part of the muscle cell called mitochondria. Our data suggests that deletion of this microRNA improves the mitochondrial function by altering levels of important mitochondrial factors. Hence, we generated mice that lack a lncRNA which regulates the expression of our microRNA, as well as mice which contain human version of the lncRNA to evaluate the clinical translation relevance of our research to T1D patients. Using novel molecules called “GapmeRs” to inhibit the human version of the lncRNA and our microRNA in humanized mice, we will assess its therapeutic potential as a treatment for T1D-associated skeletal muscle atrophy. These studies will provide a novel non-coding RNA dependent mechanistic understanding of the skeletal muscle dysfunction in T1D.