Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics

Author(s):Show less -

Campos, Juliane Cruz ; Marchesi Bozi, Luiz Henrique ; Krum, Barbara ; Grassmann Bechara, Luiz Roberto ; Ferreira, Nikolas Dresch ; Arini, Gabriel Santos ; Albuquerque, Ruda Prestes ; Traa, Annika ; Ogawa, Takafumi ; van der Bliek, Alexander M. ; Beheshti, Afshin ; Chouchani, Edward T. ; Van Raamsdonk, Jeremy M. ; Blackwell, T. Keith ; Batista Ferreira, Julio Cesar

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 120, n. 2, p. 11-pg., 2023-01-10.

Abstract

Exercise is a nonpharmacological intervention that improves health during aging and a valuable tool in the diagnostics of aging-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows a fine-tuned regulation of organelle connectiveness, size, and function. Here we have investigated the role of mitochondrial dynamics during exercise in the model organism Caenorhabditis oelegans. We show that in body-wall muscle, a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay the mitochondrial fragmentation and physical fitness decline that occur with aging. Maintenance of proper mitochondrial dynamics is essential for physical fitness, its enhancement by exercise training, and exercise-induced remodeling of the proteome. Surprisingly, among the long-lived genotypes we analyzed (isp-1,nuo-6, daf-2, eat-2, and CA-AAK-2), constitutive activation of AMP-activated protein kinase (AMPK) uniquely preserves physical fitness during aging, a benefit that is abolished by impairment of mitochondrial fission or fusion. AMPK is also required for physical fitness to be enhanced by exercise, with our findings together suggesting that exercise may enhance muscle function through AMPK regulation of mitochondrial dynamics. Our results indicate that mitochondrial connectivity and the mitochondrial dynamics cycle are essential for maintaining physical fitness and exercise responsiveness during aging and suggest that AMPK activation may recapitulate some exercise benefits. Targeting mechanisms to optimize mitochondrial fission and fusion, as well as AMPK activation, may represent promising strategies for promoting muscle function during aging. (AU)

• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/18444-9 - Mitochondrial dynamics as a limiting factor of exercise-increased healthspan in Caenorhabditis elegans
• Grantee: Juliane Cruz Campos
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 17/16540-5 - Exercise, lifespan and healthspan: a molecular and longitudinal approach to study their interactions
• Grantee: Juliane Cruz Campos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/07221-9 - Role of mitochondrial unfolded protein response (UPRmt) in doxorubicin-induced cardiomyopathy: applying comparative metabolomics to identify metabolic signatures
• Grantee: Luiz Henrique Marchesi Bozi
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 19/25049-9 - Mitochondrial formyl peptides as signaling molecules in cardiac Ischemia-reperfusion injury
• Grantee: Julio Cesar Batista Ferreira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
• Grantee: Carlos Eduardo Negrão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/09611-0 - Doxorubicin-induced cardiotoxicity: role of mitochondrial retrograde signaling activated by protein imbalance
• Grantee: Luiz Henrique Marchesi Bozi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/16694-2 - Impact of 4-hydroxinonenal on DICER regulation: a translational approach
• Grantee: Julio Cesar Batista Ferreira
• Support Opportunities: Regular Research Grants