Journal Article

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

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

2025

Overview

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. Changes in mitochondrial structure and dynamics during aging provide a mechanism for the development of age‐related sarcopenia, a condition characterized by muscle mass loss. Through the creation of three‐dimensional models of mitochondria from quadriceps muscle tissue taken from old and young humans, a loss in mitochondrial complexity was observed to occur during aging. A decrease in the expression of mitochondrial fusion protein mitofusin 2 (MFN‐2) in older populations may drive these mitochondrial structural changes. A Drosophila model with the MFN‐2 ortholog knocked down demonstrated a loss of mitochondrial complexity and lower quality cristae, which parallel changes in mitochondria observed in older humans. The use of an in vitro cell exercise model showed that the mechanism by which exercise counteracts the effects of sarcopenia, age‐related disease may be due to increased expression of MFN‐2 during exercise.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 3D reconstruction / Adult / African Americans / Age / Aged / Aged, 80 and over / Aging / Aging - metabolism / Atrophy / Biopsy / Disease / Exercise / Female / Genomics / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / Homeostasis / human skeletal muscle / Humans / Magnetic resonance imaging / Male / Metabolism / MFN‐2 / Middle Aged / Mitochondria / Mitochondria - metabolism / Mitochondria - ultrastructure / Mitochondria, Muscle - metabolism / Mitochondria, Muscle - ultrastructure / Mitochondrial DNA / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Morphology / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscle, Skeletal - ultrastructure / Musculoskeletal system / Pathology / Phenotypes / Physical fitness / Roles / Sarcopenia / Sarcopenia - metabolism / Sarcopenia - pathology / Scanning electron microscopy / Skeletal muscle