García-Domínguez, EstherGarcía-Domínguez, CristinaCabrera-Alarcón, José LuisMuñoz-Hernández, María Del MarHernansanz-Agustín, PabloCurtabbi, AndreaDomenech-Fernandez, JulioCalvo, EnriqueVázquez, JesúsSerrano, Antonio LMuñoz-Cánoves, PuraOlaso-González, GloriaEnríquez, José AntonioGómez-Cabrera, María Carmen2026-07-162026-07-162026-04-07Proc Natl Acad Sci USA. 2026 Apr 7;123(14):e2508286123.https://hdl.handle.net/20.500.12105/27599Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.We thank all the patients who have participated in the study and the members of our teams for technical help and discussions. Work in M.C.G-C. laboratory was supported by the following Grants: Instituto de Salud Carlos III CB16/10/00435 (CIBERFES) ; PID2022-142470OB-I00 and Red EXERNET-RED DE EJERCICIO FISICO Y SALUD (RED2022-134800-T) from the Spanish Ministry of Science, Innovation, and Universities; PROMETEO (CIPROM/2022/56) from Conselleria de Educacion, Universidades, y Empleo de la Generalitat Valenciana. Part of the equipment has been funded by Generalitat Valenciana and cofinanced with FEDER funds (OP FEDER of C.V. 2014-2020) .A.C. was supported by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement n. 713,673.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/frailtyhealth spanmitochondrial functionproteomicssarcopeniaAttribution-NonCommercial-NoDerivatives 4.0 International41911459PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAopen access