REMODELING AND TRANSFER OF MUSCLE MITOCHONDRIA IN HEALTH (PHYSICAL EXERCISE) AND DISEASE (NEUROGENIC MYOPATHY)

• Grant number: 24/15933-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2025
• End date: August 31, 2029
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Jones Raul Laureano Meneses
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

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 groups 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 (1, 2). This process occurs via reestablishment of the catalytic activity of mitofusins 1/2 (Mfn1/2, GTPases critical in mitochondrial fusion) in cardiac tissue. 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, Our group investigate the role of mitochondrial dynamics in the skeletal musculature in the face of physiological (physical exercise) and pathological (neurogenic myopathy) conditions. We also observed that acute physical exercise induces exacerbated mitochondrial fission, followed by mitochondrial fusion in C. elegans muscle (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 changes in liver function, 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.To track muscle mitochondrial dynamics, as well as the release of muscle mitochondria into the circulation and uptake by other tissues, we will use transgenic mice with muscle-specific expression of photoactivatable- mitoDendra2 mitochondria (PhAMflox/ACTA1Cre). To test the contribution of mitochondrial dynamics in the process of secretion and inter-tissue distribution of muscle mitochondria, we will use double transgenic mice with muscle-specific deletion of mitofusin 1/2 (Mfn1/2flox/ACTA1Cre) and muscle-specific expression of photoactivatable- mitoDendra2 mitochondria. All these animals are available in the laboratory and our preliminary data suggest a secretion of functional muscle mitochondria in the face of increased frequency of muscle contractions. (AU)