The pleiotropic role of mitochondrial calcium signalling in skeletal muscle

Description

Abstract The second messenger Ca2+ regulates a broad repertoire of cellular processes. Upon physiological stimuli, skeletal muscle mitochondria rapidly and efficiently accumulate Ca2+ into their matrix via an electrogenic pathway, that relies on the driving force of a steep electrochemical gradient. A large mt peak occurs dynamically in parallel to agonist-induced cyt increases, thanks to the activity of the Mitochondrial Calcium Uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+ accumulation. MCU positively regulates myofiber size in physiological conditions and counteracts pathological loss of skeletal muscle mass. Furthermore, skeletal muscle-specific MCU deletion inhibits mitochondrial Ca2+ uptake, impairs muscle force and exercise performance. The crucial role of mitochondrial Ca2+ is not limited to muscle fibers. Indeed, we found that MCUb, that is part of MCU complex and negatively regulates the entry of Ca2+ into mitochondria, is highly expressed in macrophages during skeletal muscle regeneration. In vitro and in vivo experiments demonstrated that MCUb absence affects macrophages skewing from a M1 to M2 profile. Coherently with the M2 pro-regenerative role, we found that regenerating muscles of MCUb KO mice, show a decrease in the expression level of myogenic regulatory transcription factors and an alteration in the reconstitution of muscle architecture after damage. In addition, co-culture experiments demonstrated that macrophage-conditioned medium from M2 MCUb KO macrophages drastically decreases satellite cell differentiation. We are currently studying the role of mitochondrial Ca2+ on satellite cells homeostasis. Our preliminary results show that the expression of the pore-forming subunit MCU does not change between quiescent and activated cells, while we observed a trend of increase of the dominant-negative subunit MCUb and of the gatekeeper MICU2, and a trend of decrease of the positive modulator of the channel MICU1 upon activation. Moreover, to understand whether satellite cells proliferation and differentiation is sensitive to mitochondrial Ca2+ homeostasis, we are generating a mouse model where MCU expression is blunted specifically in satellite cells. We will soon characterize its muscle regeneration capacity, calcium homeostasis and perform transcriptomic analysis.

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