3 <scp>D</scp> Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into <scp>MFN</scp> ‐2‐Mediated Changes

Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

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Journal
Aging Cell
Published
2025-04-25
DOI
https://doi.org/10.1111/acel.70054
Citations
11
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
8.87

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article

3 D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN ‐2‐Mediated Changes

Sepiso K. Masenga, Dhanendra Tomar, Clintoria R. Williams, Antentor Hinton et al.
11 citations
Aging Cell
Mitochondrial Function and Pathology
8.87
article

3 D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN ‐2‐Mediated Changes

Sepiso K. Masenga, Dhanendra Tomar, Clintoria R. Williams, Antentor Hinton, Anita M. Quintana, Andrea G. Marshall, Estêvão Scudese, Melanie R. McReynolds, Larry Vang, Magdalene Ameka, Estélio Henrique Martin Dantas, Innes Hicsasmaz, Anthonya Cooper, Okwute Michael Ochayi, Edgar Garza-López, Ashlesha Kadam, Jennifer Angeline Gaddy, Vineeta Sharma, Steven M. Damo, Mark Phillips, Sandra Murray, Amadou Gaye, Celestine N. Wanjalla, Duane D. Hall, Olga Y. Korolkova, Aaron Whiteside, Taylor Rodman, Blanca Rodríguez, Rahmati Rostami, Kit Neikirk, Margaret Mungai, Zer Vue, Vernat Exil, Prasanna Katti, Bret C. Mobley, Jianqiang Shao, Salma AshShareef, Bryanna Shao, Mert Demirci, Brian Glancy, Fabiana Rodrigues Scartoni, Annet Kirabo, Kinuthia Kabugi, Nelson Wandira, Dominique C. Stephens, André Kinder, Matheus Baffi, Chanel Harris, Pamela Martin, Ashton Oliver, Han Le, Revathi Dasari, Sasha Manus
article en
11 citations

Abstract

Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

Aging CellVol. 24(7)
Meharry Medical College (US), University of Iowa (US), University of Nairobi (KE), National Institutes of Health (US), Pennsylvania State University (US), Oregon State University (US), United States Department of Veterans Affairs (US), The University of Texas at El Paso (US), University of Pittsburgh (US), Wright State University (US), Vanderbilt University (US), Cornell University (US), Baze University (NG), Mulungushi University (ZM), Brazilian Academy of Sciences (BR), National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), Universidade Tiradentes (BR), VA Tennessee Valley Healthcare System (US), Faculdade de Medicina de Petrópolis (BR), Indian Institute of Science Education and Research, Tirupati (IN), Busoga University (UG), Universidade Católica de Petrópolis (BR), Wake Forest University (US), Saint Louis University (US), Universidade Federal do Estado do Rio de Janeiro (BR), Vanderbilt University Medical Center (US), Fisk University (US)
National Science Foundation, U.S. Department of Veterans Affairs, Burroughs Wellcome Fund, Silicon Valley Community Foundation, Arthritis National Research Foundation, American Heart Association, American Society of Nephrology, Bristol-Myers Squibb, Vanderbilt University, Wake Forest University, Vanderbilt Institute for Clinical and Translational Research, Indian Institute of Science, University of Pittsburgh, Oregon State University, Vanderbilt University Medical Center, Chan Zuckerberg Initiative, National Research Foundation, Indian Institute of Science Education and Research Mohali, Universidade Federal do Estado do Rio de Janeiro, Universidade Tiradentes, National Institutes of Health, Directorate for Biological Sciences, University of Texas at El Paso, Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Good health and well-being
Openalex Percentile: Top 2%
Mitochondrial Function and Pathology
8.87
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