Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity

Barbara Roman; Yusuf Mastoor; Yingfan Zhang; Dennis Gross; Danielle Springer; Chengyu Liu; Brian Glancy; Elizabeth Murphy

doi:10.1113/jp284894

journal article Nov 28, 2023

Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity

Barbara Roman

Yusuf Mastoor

Yingfan Zhang

Dennis Gross Danielle Springer Chengyu Liu

Brian Glancy

Elizabeth Murphy

The Journal of Physiology Vol. 602 No. 1 pp. 113-128 · Wiley

View at Publisher Save 10.1113/jp284894

Abstract

AbstractMitochondrial calcium concentration ([Ca2+]m) plays an essential role in bioenergetics, and loss of [Ca2+]m homeostasis can trigger diseases and cell death in numerous cell types. Ca2+ uptake into mitochondria occurs via the mitochondrial Ca2+ uniporter (MCU), which is regulated by three mitochondrial Ca2+ uptake (MICU) proteins localized in the intermembrane space, MICU1, 2, and 3. We generated a mouse model of systemic MICU3 ablation and examined its physiological role in skeletal muscle. We found that loss of MICU3 led to impaired exercise capacity. When the muscles were directly stimulated there was a decrease in time to fatigue. MICU3 ablation significantly increased the maximal force of the KO muscle and altered fibre type composition with an increase in the ratio of type IIb (low oxidative capacity) to type IIa (high oxidative capacity) fibres. Furthermore, MICU3‐KO mitochondria have reduced uptake of Ca2+ and increased phosphorylation of pyruvate dehydrogenase, indicating that KO animals contain less Ca2+ in their mitochondria. Skeletal muscle from MICU3‐KO mice exhibited lower net oxidation of NADH during electrically stimulated muscle contraction compared with wild‐type. These data demonstrate that MICU3 plays a role in skeletal muscle physiology by setting the proper threshold for mitochondrial Ca2+ uptake, which is important for matching energy demand and supply in muscle.
imageKey points
Mitochondrial calcium uptake is an important regulator of bioenergetics and cell death and is regulated by the mitochondrial calcium uniporter (MCU) and three calcium sensitive regulatory proteins (MICU1, 2 and 3).
Loss of MICU3 leads to impaired exercise capacity and decreased time to skeletal muscle fatigue.
Skeletal muscle from MICU3‐KO mice exhibits a net oxidation of NADH during electrically stimulated muscle contractions, suggesting that MICU3 plays a role in skeletal muscle physiology by matching energy demand and supply.

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Metrics

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Citations

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References

Details

Published: Nov 28, 2023
Vol/Issue: 602(1)
Pages: 113-128
License: View

Authors

B

Barbara Roman

Cardiac Physiology NHLBI, NIH Bethesda MD USA

Y

Yusuf Mastoor

Cardiac Physiology NHLBI, NIH Bethesda MD USA

Y

Yingfan Zhang

Muscle Energetics NHLBI, and NIAMS, NIH Bethesda MD USA

D

Dennis Gross

Cardiac Physiology NHLBI, NIH Bethesda MD USA

D

Danielle Springer

Mouse Phenotyping Core NHLBI, NIH Bethesda MD USA

C

Chengyu Liu

Transgenic Core NHLBI, NIH Bethesda MD USA

B

Brian Glancy

Muscle Energetics NHLBI, and NIAMS, NIH Bethesda MD USA; Transgenic Core NHLBI, NIH Bethesda MD USA

E

Elizabeth Murphy

Cardiac Physiology NHLBI, NIH Bethesda MD USA

Funding

National Heart, Lung, and Blood Institute Award: ZO1‐HL002066

Fondation Leducq Award: 16CVD04

Cite This Article

Barbara Roman, Yusuf Mastoor, Yingfan Zhang, et al. (2023). Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity. The Journal of Physiology, 602(1), 113-128. https://doi.org/10.1113/jp284894

Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity

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