Targeting GDF15-GFRAL signaling in mitochondrial myopathies

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

Project Summary Myopathy is one of the most common manifestations of mitochondrial diseases. Although genetic and bioenergetic causes of Oxidative Phosphorylation (OxPhos) impairment are well established, there is a limited understanding of the metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Our recently published studies indicate that OxPhos defective muscle initiates an integrated systemic, multiorgan metabolic response coordinated by endocrine signals, which contributes to the pathogenesis of mitochondrial myopathy. In the COX10 KO mouse model of mitochondrial myopathy, increasing plasma levels of the myokine GDF15 activate central and peripheral neurocircuits through GFRAL signaling, which over time reduce caloric intake, induce mobilization of lipid from adipose tissue, and promote energy-consuming futile cycles in muscle. This chronic GDF15-driven fat and muscle wasting result in a cachectic phenotype which aggravates the myopathy. Therefore, we hypothesize that inhibiting the GDF15-GFRAL signaling with established anti-GDF15 and anti- GFRAL antibodies will increase caloric intake, decrease lipid mobilization and attenuate energy expenditure, thus improving body weight and muscle function. In aim 1 of this application, we will target GDF15-GFRAL signaling to prevent cachexia in pre-symptomatic COX10 KO mice. In aim 2 we will target GDF15-GFRAL signaling to treat cachexia in symptomatic COX10 KO mice. This study will establish if anti-GDF15-GFRAL Ab therapy improves mitochondrial myopathy and assess whether the Ab treatment can reverse symptoms of cachexia, setting the stage for testing anti-GDF15-GFRAL Ab therapy in human mitochondrial myopathies.