Abstract
Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle loss, the efficacy of VD supplementation to overcome muscle wasting is debated. Investigations on the direct effects of VD metabolites on skeletal muscle using C2C12 myotubes have revealed an unexpected pro-atrophic activity of calcitriol (1,25VD), while its upstream metabolites cholecalciferol (VD3) and calcidiol (25VD) have anti-atrophic effects. Here, we investigated if the atrophic effects of 1,25VD on myotubes depend on its activity on mitochondrial metabolism. The impact of 1,25VD and its upstream metabolites VD3 and 25VD on mitochondria dynamics and the activity of C2C12 myotubes was evaluated by measuring mitochondrial content, architecture, metabolism, and reactive oxygen species (ROS) production. We found that 1,25VD induces atrophy through protein kinase C (PKC)-mediated ROS production, mainly of extramitochondrial origin. Consistent with this, cotreatment with the antioxidant N-acetylcysteine (NAC), but not with the mitochondria-specific antioxidant mitoTEMPO, was sufficient to blunt the atrophic activity of 1,25VD. In contrast, VD3 and 25VD have antioxidant properties, suggesting that the efficacy of VD supplementation might result from the balance between atrophic pro-oxidant (1,25VD) and protective antioxidant (VD3 and 25VD) metabolites.
Highlights
The progressive loss of muscle strength and functionality that characterizes different physiological and pathological statuses is thought to be due to alterations in mitochondria, including reduced mitochondrial content, impaired oxidative capacity, and increased oxidative damage [1,2,3,4,5].As a deficit of vitamin D is often associated with these muscle-affecting conditions, vitamin D supplementation has been proposed as a potential treatment to improve muscle strength, albeit with conflicting results
To test the hypothesis that 1,25-hydroxyvitamin D3 (25VD) impinges on C2C12 mitochondrial function, we investigated its effects on mitochondrial membrane potential
In agreement with the proatrophic effects of 1,25VD [18], we observed that 1,25VD induced the loss of mitochondrial membrane potential in C2C12 myotubes, highlighted by a fluorescence red-to-green emission shift of the cationic dyes JC-1 (Figure 1a,b)
Summary
The progressive loss of muscle strength and functionality that characterizes different physiological (aging) and pathological (sarcopenia, cachexia, idiopathic chronic fatigue, myasthenia gravis) statuses is thought to be due to alterations in mitochondria, including reduced mitochondrial content, impaired oxidative capacity, and increased oxidative damage [1,2,3,4,5].As a deficit of vitamin D is often associated with these muscle-affecting conditions, vitamin D supplementation has been proposed as a potential treatment to improve muscle strength, albeit with conflicting results. The progressive loss of muscle strength and functionality that characterizes different physiological (aging) and pathological (sarcopenia, cachexia, idiopathic chronic fatigue, myasthenia gravis) statuses is thought to be due to alterations in mitochondria, including reduced mitochondrial content, impaired oxidative capacity, and increased oxidative damage [1,2,3,4,5]. Several works have investigated the effects of vitamin D on mitochondrial function in muscle-derived cells. The treatment of both human primary and C2C12 myoblasts with 1α,25-dihydroxyvitamin D3 (1,25VD) increases mitochondrial function [13,14,15]. This activity of 1,25VD on mitochondria is even effective in mitigating
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