Vitamin D deficiency selectively exacerbates mitochondrial dysfunction in receptor-rich soleus muscle during disuse-induced atrophy

This study investigated the role of vitamin D (VD) in disuse skeletal muscle atrophy, with a particular focus on muscle type-specific differences. Male C57BL/6 J mice were fed either a standard or VD-deficient diet and subjected to hindlimb immobilization to induce disuse atrophy. The expression of vitamin D receptor (VDR) was analyzed across several skeletal muscles, and muscle fiber atrophy and mitochondrial function were evaluated. In addition, cultured C2C12 myotubes were used to assess the direct effects of VD on oxidative stress-induced mitochondrial dysfunction. VDR expression was markedly higher in the soleus (SOL) muscle than in other muscles at both mRNA and protein levels. VD deficiency selectively exacerbated immobilization-induced atrophy solely in the SOL muscle, characterized by a significant reduction in muscle fiber cross-sectional area and downregulation of mitochondria-related genes (Pgc1α, Cox1, Cox5b, Cytb, Sdha). Consistently, mitochondrial function, which was assessed based on succinate dehydrogenase activity, further decreased in the VD-deficient SOL muscle. In contrast, the gastrocnemius (GC) and tibialis anterior (TA) muscles showed no significant VD-dependent changes. In C2C12 myotubes, active VD [1,25(OH)₂VD₃] attenuated hydrogen peroxide-induced reductions in mitochondrial gene expression and mitochondrial DNA content, suggesting a direct protective role of VD in muscle cells. Taken together, these findings demonstrate that VD deficiency aggravates disuse muscle atrophy through impaired mitochondrial function, particularly in muscles with high VDR expression, such as the SOL. The study highlights muscle type-specific vulnerability to VD deficiency and suggests that VD supplementation can protect certain muscles from disuse-induced atrophy.