Abstract P806: Sirtuin1 Plays a Critical Role in Reversing Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

Abstract

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that severely induces muscle wasting and weakness, which contributes more to the long-term functional disability in stroke patients than any other disease. Currently, no approved pharmacological drug is available to treat stroke-induced muscle loss. Rehabilitative therapy is the only available option to improve muscle function in stroke patients. However, higher muscle fatigability and lower muscle strength from extensive muscle wasting in post-stroke patients provide poor rehabilitative outcomes. As a result, about two-thirds of stroke survivors persist in a state of insufficient recovery and experience physical disability that drastically reduces their health and quality of life. The major challenge in the drug discovery effort for treating post-stroke muscle wasting is the lack of our understanding of the molecular and/or cellular mechanisms that underlie the muscle wasting in stroke. To understand the molecular origin of stroke-induced muscle atrophy, gene expression profiling and associated biological pathway enrichment studies were performed in a mouse model of cerebral ischemic stroke using high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq data revealed that the elevated atrophy in skeletal muscle observed in response to stroke was primairly associated with the altered expression of genes involved in the muscle protein degradation pathway. Further analysis of RNA-seq data identified Sirtuin1 (SirT1) as a critical protein that plays a significant role in regulating post-stroke muscle mass. SirT1 gain-of-function in skeletal muscle significantly reversed stroke-induced muscle atrophy via inhibiting the activation of the ubiquitin proteasomal pathway and restoring autophagy function. Collectively, this study identified suppression of SirT1as a novel mechanism by which stroke induces muscle atrophy.