Remodelling of Skeletal Muscle Myosin Metabolic States in Hibernating Mammals

Lewis, C. T. A.; Melhedegaard, E. G.; Ognjanovic, M. M.; Olsen, M. S.; Laitila, J.; Seaborne, R. A. E.; Gronset, M. N.; Zhang, C.; Iwamoto, H.; Hessel, A. L.; Kuehn, M. N.; Merino, C.; Amigo, N.; Frobert, O.; Giroud, S.; Staples, J. F.; Goropashnaya, A. V.; Fedorov, V. B.; Barnes, B. M.; Toien, O.; Drew, K. L.; Sprenger, R. J.; Ochala, J.

doi:10.1101/2023.11.14.566992

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bioRxiv · 10.1101/2023.11.14.566992

Remodelling of Skeletal Muscle Myosin Metabolic States in Hibernating Mammals

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Abstract

Hibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators, Ictidomys tridecemlineatus and Eliomys quercinus and larger hibernators, Ursus arctos and Ursus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure in U. arctos and U. americanus during hibernation, whilst in I. tridecemlineatus and E. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20{degrees}C). Upon repeating loaded Mant-ATP chase experiments at 8{degrees}C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77-107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor in I. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.

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Lewis, C. T. A., Melhedegaard, E. G., Ognjanovic, M. M., Olsen, M. S., Laitila, J., Seaborne, R. A. E., Gronset, M. N., Zhang, C., Iwamoto, H., Hessel, A. L., Kuehn, M. N., Merino, C., Amigo, N., Frobert, O., Giroud, S., Staples, J. F., Goropashnaya, A. V., Fedorov, V. B., Barnes, B. M., Toien, O., Drew, K. L., Sprenger, R. J., Ochala, J.. 2023-11-16. Remodelling of Skeletal Muscle Myosin Metabolic States in Hibernating Mammals. https://doi.org/10.1101/2023.11.14.566992

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