Muscle-liver metabolic miscommunication in a genetic model of mitochondrial myopathy

Abstract

Mitochondrial myopathy is a devastating disorder with no treatment available. The pathology of mitochondrial myopathy is characterized by an initial skeletal muscle degeneration due to mitochondrial dysfunction followed by a multi systemic effect such as lipolysis, gluconeogenesis, starvation-like response, among others, which contributes to disease progression and lethality. Targeting the inter-organ communication triggered by mitochondrial myopathy is a promising approach to avoid the systemic consequences of mitochondrial dysfunction in skeletal muscle. However, little is known about factors secreted by skeletal muscle that can act as signaling molecules in this inter-organ communication. Here we plan to use a murine model of mitochondrial myopathy to identify potential skeletal muscle candidates for inter-organ communication in mitochondrial myopathy. Our preliminary findings suggest that deletion of mitofusins 1 and 2 (skMFN1/2-/-) in skeletal muscle causes mitochondrial myopathy. These animals display mitochondrial dysfunction, exercise intolerance, severe sarcopenia characterized by body weight loss, muscle atrophy, and fibrosis, and reduced lifespan when compared with wildtype littermates (skMFN1/2+/+). skMFN1/2-/- mice have systemic metabolic remodeling depicted by reduced body fat mass, increased circulating lipids, glucose intolerance, insulin resistance, lactic acidosis, and elevated baseline energy expenditure. The liver has a central role in metabolic and energetic homeostasis. As such, we reasoned that this tissue could be affected by mitochondrial myopathy. In fact, there is a reduction in fat mass and glycogen content in the liver of skMFN1/2-/- mice. Biochemically, the liver from skMFN1/2-/- mice has impaired mitochondrial dynamics, autophagy and endoplasmatic reticulum stress response. When we subjected to high-fat diet (60%), skMFN1/2-/- mice displayed a substantial reduction in lifespan and higher hepatic lipid deposition when compared to WT. Collectively, our findings suggest that mitochondrial myopathy is sufficient to impair muscle-liver communication leading to a substantial reduction of lifespan. However, the factors involved in this muscle-liver endocrine signaling remain unclear. Considering the role of metabolites in systemic metabolic homeostasis and inter-organ communication, we decided to apply comparative metabolomics to identify metabolites responsible for muscle-liver (mis)communication in this murine model of mitochondrial myopathy. The current research proposal is a joint effort between the labs of Dr. Julio Ferreira (USP) and Dr. Evanna Mills (Dana-Farber Cancer Institute - Harvard Medical School). Dr. Mills' lab focuses on unraveling how metabolites act as signaling molecules to regulate homeostasis and its role in chronic pathologies such as metabolic disease, chronic inflammatory disease, and cancer. Therefore, this international cooperation will allow us to investigate the metabolites involved in muscle-liver (mis)communication in a murine model of mitochondrial myopathy.