Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise

Ryan J Allen; Ana Kronemberger; Qian Shi; R Marshall Pope; Elizabeth Cuadra-Muñoz; Wangkuk Son; Long-Sheng Song; Ethan J Anderson; Renata O Pereira; Vitor A Lira

doi:10.1111/acel.70137

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Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise

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Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise

Ryan J Allen, Ana Kronemberger, Qian Shi, R Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira and Vitor A Lira

Aging cell, Vol.24(9), e70137

09/2025

DOI: 10.1111/acel.70137

PMCID: PMC12419855

PMID: 40586781

Appears in UI Libraries Support Open Access

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Abstract

Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres, forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice, we reveal that aging slows muscle relaxation, leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We also demonstrate that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are affected early in aging and are closely associated with the rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca homeostasis, cytoskeleton integrity, and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.

Aging

Exercise

mitochondria

mitochondrial?associated ER membranes

skeletal muscle

endoplasmic reticulum

sarcoplasmic reticulum

sarcopenia

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Title: Subtitle: Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise
Creators: Ryan J Allen - University of Iowa
Ana Kronemberger - University of Iowa
Qian Shi - Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
R Marshall Pope - University of Iowa
Elizabeth Cuadra-Muñoz - Department of Health and Human Physiology, Fraternal Order of Eagles Diabetes Research Center, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa, USA
Wangkuk Son - Department of Health and Human Physiology, Fraternal Order of Eagles Diabetes Research Center, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa, USA
Long-Sheng Song - Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Ethan J Anderson - Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA
Renata O Pereira - Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Vitor A Lira - University of Iowa
Resource Type: Journal article
Publication Details: Aging cell, Vol.24(9), e70137
DOI: 10.1111/acel.70137
PMID: 40586781
PMCID: PMC12419855
NLM abbreviation: Aging Cell
ISSN: 1474-9726
eISSN: 1474-9726
Publisher: Wiley
Grant note: R01HL167087 / NIH HHS R56AG068320 / NIH HHS HL130346 / NIH HHS HL157741 / NIH HHS DK125405 / NIH HHS 20SFRN35200003 / American Heart Association HL157781 / NIH HHS R56AG080101 / NIH HHS
Language: English
Electronic publication date: 06/30/2025
Date published: 09/2025
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Dental Research; Medicine Administration; Endocrinology and Metabolism; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984838677202771

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