Skeletal Muscle and Liver Communication in Mitochondrial Myopathy

Mitochondrial diseases (MD) encompass a group of devastating disorders for which effective treatments are lacking. MD often affects skeletal muscle, a tissue with high energy demand. While the degenerative effects of MD on skeletal muscle have been extensively studied, the metabolic and energetic responses driven by mitochondrial myopathies remain poorly understood. In this study, we characterize glucose and lipid metabolism and energetic homeostasis in wild-type and skeletal muscle-specific (inducible) mitofusins 1 and 2 (MFN1/2) double-knockout mice. Experiments were conducted using male mice aged 8-12 weeks, housed in a temperature-controlled room on a 12-hour light/dark cycle, and fed either a standard chow or a high-fat (60%) diet. Our findings show that after 2 weeks of deletion, MFN1/2-ko mice under a standard chow diet display several features of mitochondrial myopathy, including impaired skeletal muscle mitochondrial bioenergetics, skeletal muscle degeneration, elevated circulating lactate levels, and exercise intolerance. At this stage, mitochondrial myopathy culminated in progressive weight loss, reduction in both lean and fat mass, and increase in basal energy expenditure, heart rate, and respiratory frequency. Collectively, these data suggest that mitochondrial myopathy induces hypermetabolism in MFN1/2-ko mice. Notably, conditional deletion of MFN1/2 results in hypoglycemia, glucose intolerance, insulin resistance, and a progressive decrease in circulating triglycerides. Considering the liver plays a central role in metabolic and energetic homeostasis; we assessed liver function in these mice. MFN1/2-ko mice under a standard chow diet displayed decreased fat mass and glycogen content in the liver with no signs of tissue damage. Biochemical analysis revealed impaired mitochondrial dynamics, autophagy, and endoplasmic reticulum stress response in the liver of MFN1/2-ko mice, suggesting an inter-organ communication between skeletal muscle and liver during the progression of mitochondrial myopathy. Finally, after 4 weeks on a high-fat diet, we observed increased circulating cholesterol, triglycerides, and glucose only in MFN1/2-ko mice. Interestingly, MFN1/2-ko mice were protected from hepatic fat accumulation induced by the high-fat diet. Together, these results suggest that mitochondrial myopathy drives an early metabolic and energetic response in mice. Moreover, unraveling the inter-organ communication between skeletal muscle and liver might provide an underappreciated mechanism that orchestrates the systemic degenerative effects of mitochondrial myopathy. FAPESP: 2021/09608-8; 2022/10579-5; 2024/01696-3 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.