The mitochondrial calcium uniporter underlies metabolic fuel preference in skeletal muscle.

Autor: Kwong JQ; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.; Department of Pediatrics, Division of Cardiovascular Biology, Emory University School of Medicine, Atlanta, Georgia, USA., Huo J; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA., Bround MJ; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA., Boyer JG; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA., Schwanekamp JA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA., Ghazal N; Department of Pediatrics, Division of Cardiovascular Biology, Emory University School of Medicine, Atlanta, Georgia, USA., Maxwell JT; Department of Pediatrics, Division of Cardiovascular Biology, Emory University School of Medicine, Atlanta, Georgia, USA., Jang YC; School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA., Khuchua Z; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.; Sechenov University, Moscow, Russia., Shi K; Department of Bioengineering, University of Washington, Seattle, Washington, USA., Bers DM; Department of Pharmacology, University of California, Davis, California, USA., Davis J; Department of Bioengineering, University of Washington, Seattle, Washington, USA., Molkentin JD; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.; Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2018 Nov 15; Vol. 3 (22). Date of Electronic Publication: 2018 Nov 15.
DOI: 10.1172/jci.insight.121689
Abstrakt: The mitochondrial Ca2+ uniporter (MCU) complex mediates acute mitochondrial Ca2+ influx. In skeletal muscle, MCU links Ca2+ signaling to energy production by directly enhancing the activity of key metabolic enzymes in the mitochondria. Here, we examined the role of MCU in skeletal muscle development and metabolic function by generating mouse models for the targeted deletion of Mcu in embryonic, postnatal, and adult skeletal muscle. Loss of Mcu did not affect muscle growth and maturation or otherwise cause pathology. Skeletal muscle-specific deletion of Mcu in mice also did not affect myofiber intracellular Ca2+ handling, but it did inhibit acute mitochondrial Ca2+ influx and mitochondrial respiration stimulated by Ca2+, resulting in reduced acute exercise performance in mice. However, loss of Mcu also resulted in enhanced muscle performance under conditions of fatigue, with a preferential shift toward fatty acid metabolism, resulting in reduced body fat with aging. Together, these results demonstrate that MCU-mediated mitochondrial Ca2+ regulation underlies skeletal muscle fuel selection at baseline and under enhanced physiological demands, which affects total homeostatic metabolism.
Databáze: MEDLINE