The role of testosterone in the regulation of mitochondrial calcium signalling in skeletal muscle

The Mitochondrial Calcium Uniporter (MCU) is the channel that allows the selective entry of calcium into the mitochondrial matrix (Baughman, Perocchi, Girgis, Plovanich, Belcher-Timme, et al., 2011; De Stefani et al., 2011) regulating muscle trophism and metabolism (Altamimi et al., 2019; Debattisti et al., 2019; Gherardi et al., 2019, 2025; Huo et al., 2023; Logan et al., 2014; Mammucari et al., 2015). However, loss of MICU1-dependent MCU regulation disrupts proper channel function, causing excessive mitochondrial calcium entry that triggers mitochondrial dysfunction and myopathy (Debattisti et al., 2019; Logan et al., 2014). Testosterone is an androgenic steroid hormone with anabolic effects, promoting muscle hypertrophy and strength (Estrada et al., 2003; M. Vicencio et al., 2011; Urban, 2011), through both genomic (Bricout VA et al., 1994) and non-genomic mechanisms (Estrada et al., 2003; M. Vicencio et al., 2011). Moreover, testosterone impinges on mitochondrial biogenesis and function (Tian et al., 2023). The significance of testosterone is emphasised by the detrimental effects of its deficiency. While the harmful impact of hypogonadism on muscle mass is well documented, the exact underlying mechanisms remain largely unexplored. Recently, testosterone has been recognised as a positive modulator of mitCa2+ uptake (De Mario et al., 2021 and unpublished data). Here, we aimed to investigate whether testosterone modulates mitCa2+ uptake in skeletal muscle and to explore the impact of both acute and prolonged testosterone depletion on mitCa2+ homeostasis, muscle trophism, and mitochondrial function. While in the short-term testosterone acutely increased mitCa2+ uptake regulating oxidative metabolism, prolonged surgical castration caused abnormal mitCa2+ entry, leading to mitochondrial dysfunction and muscle atrophy. MCU haploinsufficiency in MCU+/- and skeletal muscle-specific MCU+/- (skMCU+/-) mouse lines rescued this phenotype, indicating a causative role for mitCa2+ derangement in castration-induced atrophy.