Mitochondrial dynamics in skeletal muscle: role of mitofusin 1 in health (exercise) and disease (neurogenic myopathy)

• Grant number: 23/10054-2
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date until: August 01, 2023
• End date until: July 31, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Agreement: CNPq
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Willian das Neves Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/01576-5 - Mitochondrial dynamics in skeletal muscle: role of mitofusin 1 in health (exercise) and disease (neurogenic myopathy), AP.R

Abstract

Mitochondria are organelles that continually undergo fission and fusion (mitochondrial dynamics). These opposing processes work together to maintain mitochondrial shape, size, number and function. Disruption of mitochondrial dynamics results in the accumulation of fragmented and dysfunctional mitochondria, contributing to the establishment and progression of several degenerative diseases. Our group have demonstrated that reestablishing the mitochondrial fission-fusion balance through sustained physical exercise or selective pharmacological therapy is sufficient to recover mitochondrial bioenergetics and improve the prognosis of heart failure in rodents. Considering that skeletal muscle has a high metabolic demand and a large number of mitochondria, and that muscle diseases are often accompanied by mitochondrial dysfunction, we decided to investigate the role of mitochondrial dynamics in the current project FAPESP 2021/09484-7 (to which this proposal is linked) in the skeletal musculature in the face of physiological (physical exercise) and pathological (neurogenic myopathy) conditions. We observed that acute physical exercise induces exacerbated mitochondrial fission, followed by mitochondrial fusion in C. elegans muscle (3). Furthermore, we demonstrate that muscular proteome remodeling and adaptation to chronic physical exercise depends on mitochondrial fission-fusion (3). Recently, we have validated in rodents the importance of mitochondrial dynamics to skeletal muscle biology. Muscle-specific deletion of mitofusins (Mfn1/2) results in loss of muscle mass and function in mice. Furthermore, we observed that these animals have exacerbated liver dysfunction, suggesting that disrupted skeletal muscle mitochondrial dynamics affects the functioning of other organs. However, the mechanisms involved in this communication between systems are still elusive. Our collaborators have recently discovered that mitochondria are secreted by different cell types, including astrocytes and microglia; being a process dependent on mitochondrial dynamics, and which exerts an important role on tissue-tissue communication and neurodegeneration (4). These findings supporting the role of extracellular mitochondria in inter-tissue communication are strengthened by clinical data, where heterologous mitochondria transplantation results in an increase in the number of circulating free mitochondria and consequent improvement in the prognosis of patients with multisystemic syndrome (5). Considering that skeletal muscle represents the largest reserve of mitochondria in the body, we hypothesize that muscle mitochondria secreted to circulation play an important role in communication between tissues. Furthermore, we hypothesized that the state of activity and trophism of muscles, as well as the functioning of muscle mitochondrial dynamics, affect this tissue-tissue communication mediated by muscle mitochondria secreted to the circulation. In this sense, the current proposal aims to expand the horizons on the role of muscle mitochondrial dynamics in inter-tissue communication. For this, we propose to 1. Characterize in real time the process of mitochondrial fusion-fission in the skeletal muscles of mice, 2. Track the secretion of muscle mitochondria into the bloodstream; 3. Determine the distribution/uptake of these muscle mitochondria in the circulation by other tissues; and 4. Assess the morphological and bioenergetic characteristics of muscle circulating mitochondria. All these measurements will be carried out in different experimental conditions (see schematic model of the proposal for details) using wild-type animals and animals with muscle mitochondrial dynamics loss-of-function.