Mitochondrial dynamics in skeletal muscle: role of mitofusin 1 in health and disease

Abstract

Mitochondria are organelles that continually undergo fusion and fission. These opposite processes work together to maintain the shape, size, number and function of mitochondria. Recently, our group demonstrated that reestablishing mitochondrial fusion-fission balance through exercise or drug therapy is sufficient to restore mitochondrial bioenergetics and improves the prognosis of heart failure in rodents. This process occurs throughout the re-establishment of catalytic activity of mitofusin 1 (Mfn1, an important GTPase in mitochondrial fusion) in cardiac tissue. Considering that skeletal muscles present a high metabolic demand and a large amount of mitochondria, and that muscle diseases are frequently accompanied by mitochondrial dysfunction, we decided to follow up our previous studies and investigate the role of mitochondrial plasticity (ability to reorganize its morphology and number under stress) in skeletal muscle. Our preliminary results using C. elegans show that mitochondrial plasticity is also important in skeletal muscle and depends directly on Mfn1. C. elegans deficient for Mfn1 have impaired mitochondrial bioenergetics and physical intolerance.In this sense, we propose in the present research project 1. Characterize in real time the process of mitochondrial fusion-fission in rodent skeletal muscles, and 2. Study the role of Mfn1 in mitochondrial plasticity (including fusion, fission and clearance - by autophagy), bioenergetics and morphological function of skeletal muscle at baseline and upon physiological (acute and chronic physical exercise) and pathological (neurogenic myopathy) stimuli. Both stimuli are already established in our laboratory. For this, we will use double transgenic mice with inducible muscle-specific mitofusin 1 deletion (Mfn1flox/ACTA1Cre) and photoactivatable mitochondria (PhAMflox/ACTA1Cre) expression. PhAM animals will be of great importance for the characterization of real-time mitochondrial fusion-fission in skeletal muscle. Finally, we will use three-dimensional electron microscopy to validate mitochondrial fusion-fission findings in skeletal muscle. A better understanding of this process may contribute to the development and use of new pharmacological and non-pharmacological strategies able to counteract muscle dysfunction and degeneration. For this project, we will count on the collaboration of Profs. Ling Qi (University of Michigan, USA), Alexander van der Bliek (UCLA, USA), Daria Mochly-Rosen (Stanford University, USA) and Alicia Kowaltowski (IQ-USP). (AU)