Loss of mitochondrial calcium uniporter rewires skeletal muscle metabolism and substrate preference

Abstract

Skeletal muscle mitochondria readily accumulate Ca 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 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 uptake, impairs muscle force and exercise performance, and determines a slow to fast switch in MHC expression. Mitochondrial Ca 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 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.

A High-Throughput Screening Identifies MICU1 Targeting Compounds

“…We show here that treatment with MCU-i4 and MCU-i11 inhibits myotube growth, in line with the role of MCU complex on skeletal muscle mass and function (Debattisti et al, 2019;Gherardi et al, 2019;Mammucari et al, 2015;Zampieri et al, 2016). In various other different settings, these compounds may serve as tools to modulate mitochondrial Ca 2+ -entry-dependent events.…”

“…Direct binding of these molecules to MICU1 was essential for their activity. Both compounds reduced mitochondrial Ca 2+ uptake in isolated myofibers from mouse flexor digitorum brevis (FDB) muscles and, in agreement with the role of MCU complex in skeletal muscle trophism (Debattisti et al, 2019;Gherardi et al, 2019;Mammucari et al, 2015), prevented myotube growth.…”

“…In various other different settings, these compounds may serve as tools to modulate mitochondrial Ca 2+ -entry-dependent events. Similarly to MCU deletion (Gherardi et al, 2019), negative modulators of Ca 2+ uptake may modulate mitochondrial metabolism and substrate preference in the skeletal muscle.…”

“…Both MCU-i4 and MCU-i11 inhibited mitochondrial Ca 2+ uptake in myofibers ( Figure 5C). Next, given that genetic inhibition of mitochondrial Ca 2+ uptake has been shown to decrease muscle mass (Debattisti et al, 2019;Gherardi et al, 2019;Mammucari et al, 2015), we used these two compounds in a well-established in vitro model mimicking myotube growth. For this purpose, we treated C2C12 myotubes with MCU-i4 and MCU-i11, respectively.…”

Protein composition of the muscle mitochondrial reticulum during postnatal development

“…; Gherardi et al . ). However, the regulation of mitochondrial calcium uptake during muscle development remains unknown.…”