2. Academic Validation
  3. ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle

ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle

  • bioRxiv. 2026 Mar 28:2026.03.27.711928. doi: 10.64898/2026.03.27.711928.
Amber Crabtree 1 2 3,  Mohd Mabood Khan 4,  Estevão Scudese 1,  Calixto Pablo Hernandez Perez 1,  Prasanna Venkhatesh 5,  Andrea G Marshall 1 6,  Benjamin Rodriguez 1,  Edgar Garza López 7 6,  Okwute M Ochayi 8,  Estélio Henrique Martin Dantas 9 10 11 12 13,  Pamela Martin 6,  Matheus Baffi 14,  Fabiana Scartoni 9,  Margaret Mungai 1 7 15,  Kit Neikirk 1 16,  Jennifer Streeter 7 15,  Renata O Pereira 7 15,  Dao Fu Dai 17,  Han Le 1,  Harrison Mobley 1,  Jeremiah Afolabi 4,  Bret C Mobley 18,  Celestine N Wanjalla 19,  Duane Hall 7,  Julia D Berry 18,  Oleg Kovtun 20,  Jenny C Schafer 21,  Sean Schaffer 21,  Prasanna Katti 5,  Chantell Evans 22,  André Kinder 23,  Joyonna Gamble-George 24 25,  Melanie McReynolds 4,  Annet Kirabo 4,  Sepiso K Masenga 1 4,  Antentor O Hinton Jr 1 6
Affiliations

Affiliations

  • 1 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA.
  • 2 The Frist Center for Autism and Innovation, Vanderbilt University, Nashville, Tennessee, USA.
  • 3 Department of Physics and Astronomy, Vanderbilt University, Nashville, Tennessee, USA.
  • 4 Department of Medicine, Division of Genetic Medicine & Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 5 Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, AP, 517619, India.
  • 6 Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208-3501, USA.
  • 7 Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242.
  • 8 Department of Physiology, Faculty of Basic Medical Sciences, Baze University Abuja, Nigeria.
  • 9 Laboratory of Biosciences of Human Motricity (LABIMH) of the Federal University of State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil.
  • 10 Doctor's Degree Program in Nursing and Biosciences - PpgEnfBio, Federal University of the State of Rio de Janeiro - UNIRIO, Rio de Janeiro, RJ, Brazil.
  • 11 Laboratory of Human Motricity Biosciences - LABIMH, Federal University of the State of Rio de Janeiro - UNIRIO, RJ, Brazil.
  • 12 Brazilian Paralympic Academy - APB, Brazil.
  • 13 Doctor's Degree Program in Health and Environment - PSA, Tiradentes University - UNIT, Aracaju, SE, Brazil.
  • 14 Sport Sciences and Exercise Laboratory (LaCEE), Catholic University of Petrópolis (UCP), Brazil.
  • 15 Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242.
  • 16 Department of Biology, University of Hawaii at Hilo, Hilo, HI, 96720, USA.
  • 17 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 18 Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 19 Division of Infection Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 20 Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA.
  • 21 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.
  • 22 Department of Cell Biology, Duke University School of Medicine, Durham, NC, 27708, USA.
  • 23 Artur Sá Earp Neto University Center (UNIFASE-FMP), Petrópolis Medical School, Petrópolis, RJ, Brazil.
  • 24 Department of Computer Science, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • 25 Environmental Sciences Graduate Program, Oregon State University, Corvalis, OR, USA.
PMID: 41929138 DOI: 10.64898/2026.03.27.711928
Abstract

Aging is associated with a progressive loss of skeletal muscle function, known as sarcopenia; however, the molecular mechanisms coordinating cellular stress responses and structural adaptations permissive of sarcopenia remain incompletely understood. In our previous studies, we found aging differentially impacted mitochondrial networks by muscle, suggesting unique stress thresholds and response activation. Here, we investigate the role of activating transcription factor 4 (ATF4), a master regulator of the integrated stress response (ISR), in aged quadriceps muscle using complementary patient and aging mouse models. Older adults exhibited a marked decrease in aerobic capacity, muscle strength, and endurance when compared with young participants. These results paralleled findings in aged mice, with significant loss of muscle mass across multiple hindlimb muscles. Ultrastructural analysis revealed substantial age-related changes in mitochondrial morphology, including increased volume, surface area, and branching index, as well as a shift toward larger, more complex mitochondria. Our data indicate that ATF4 binds directly to the promoter region of the gene encoding TFAM, suggesting a transcriptional regulatory relationship to support DNA stability. These structural and transcriptional changes likely impair oxidative capacity and drive a feed-forward cycle of mitochondrial dysfunction and ISR activation. Our findings indicate that ATF4 coordinates transcriptomic and structural adaptations in aging muscle, identifying the ISR pathway as a potential therapeutic target for preserving muscle function in older adults.

Keywords

3D Structure; ATF4; Aging; Metabolism; Mitochondria; Muscle; Skeletal.

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