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Loss of mitochondrial calcium uniporter rewires skeletal muscle metabolism and substrate preference
- Source :
- Cell Death and Differentiation; February 2019, Vol. 26 Issue: 2 p362-381, 20p
- Publication Year :
- 2019
-
Abstract
- Skeletal muscle mitochondria readily accumulate Ca2+in response to SR store-releasing stimuli thanks to the activity of the mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+uptake. MCU positively regulates myofiber size in physiological conditions and counteracts pathological loss of muscle mass. Here we show that skeletal muscle-specific MCU deletion inhibits myofiber mitochondrial Ca2+uptake, impairs muscle force and exercise performance, and determines a slow to fast switch in MHC expression. Mitochondrial Ca2+uptake is required for effective glucose oxidation, as demonstrated by the fact that in muscle-specific MCU−/−myofibers oxidative metabolism is impaired and glycolysis rate is increased. Although defective, mitochondrial activity is partially sustained by increased fatty acid (FA) oxidation. In MCU−/−myofibers, PDP2 overexpression drastically reduces FA dependency, demonstrating that decreased PDH activity is the main trigger of the metabolic rewiring of MCU−/−muscles. Accordingly, PDK4 overexpression in MCUfl/flmyofibers is sufficient to increase FA-dependent respiration. Finally, as a result of the muscle-specific MCU deletion, a systemic catabolic response impinging on both liver and adipose tissue metabolism occurs.
Details
- Language :
- English
- ISSN :
- 13509047 and 14765403
- Volume :
- 26
- Issue :
- 2
- Database :
- Supplemental Index
- Journal :
- Cell Death and Differentiation
- Publication Type :
- Periodical
- Accession number :
- ejs48109739
- Full Text :
- https://doi.org/10.1038/s41418-018-0191-7