| First Author | Gherardi G | Year | 2019 |
| Journal | Cell Death Differ | Volume | 26 |
| Issue | 2 | Pages | 362-381 |
| PubMed ID | 30232375 | Mgi Jnum | J:277727 |
| Mgi Id | MGI:6342377 | Doi | 10.1038/s41418-018-0191-7 |
| Citation | Gherardi G, et al. (2019) Loss of mitochondrial calcium uniporter rewires skeletal muscle metabolism and substrate preference. Cell Death Differ 26(2):362-381 |
| abstractText | Skeletal muscle mitochondria readily accumulate Ca(2+) in response to SR store-releasing stimuli thanks to the activity of the mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca(2+) 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 Ca(2+) uptake, impairs muscle force and exercise performance, and determines a slow to fast switch in MHC expression. Mitochondrial Ca(2+) 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 MCU(fl/fl) myofibers 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. |
