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SR Ca2+ leak in skeletal muscle fibers acts as an intracellular signal to increase fatigue resistance.
Karolinska Institutet.
Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.ORCID iD: 0000-0002-0642-4838
Karolinska Institutet.
Karolinska Institutet.
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2019 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 151, no 4, p. 567-577, article id jgp.201812152Article in journal (Refereed) Published
Abstract [en]

Effective practices to improve skeletal muscle fatigue resistance are crucial for athletes as well as patients with dysfunctional muscles. To this end, it is important to identify the cellular signaling pathway that triggers mitochondrial biogenesis and thereby increases oxidative capacity and fatigue resistance in skeletal muscle fibers. Here, we test the hypothesis that the stress induced in skeletal muscle fibers by endurance exercise causes a reduction in the association of FK506-binding protein 12 (FKBP12) with ryanodine receptor 1 (RYR1). This will result in a mild Ca2+ leak from the sarcoplasmic reticulum (SR), which could trigger mitochondrial biogenesis and improved fatigue resistance. After giving mice access to an in-cage running wheel for three weeks, we observed decreased FKBP12 association to RYR1, increased baseline [Ca2+]i, and signaling associated with greater mitochondrial biogenesis in muscle, including PGC1α1. After six weeks of voluntary running, FKBP12 association is normalized, baseline [Ca2+]i returned to values below that of nonrunning controls, and signaling for increased mitochondrial biogenesis was no longer present. The adaptations toward improved endurance exercise performance that were observed with training could be mimicked by pharmacological agents that destabilize RYR1 and thereby induce a modest Ca2+ leak. We conclude that a mild RYR1 SR Ca2+ leak is a key trigger for the signaling pathway that increases muscle fatigue resistance.

Place, publisher, year, edition, pages
Rockefeller University Press, 2019. Vol. 151, no 4, p. 567-577, article id jgp.201812152
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Physiology
Research subject
Medicine/Technology
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URN: urn:nbn:se:gih:diva-5547DOI: 10.1085/jgp.201812152ISI: 000462865900016PubMedID: 30635368OAI: oai:DiVA.org:gih-5547DiVA, id: diva2:1279231
Available from: 2019-01-16 Created: 2019-01-16 Last updated: 2019-04-23Bibliographically approved

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Mattsson, C. MikaelEkblom, Björn

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