Vitamin D Promotes Skeletal Muscle Regeneration and Mitochondrial Health

Abstract

Vitamin D is an essential nutrient for the maintenance of skeletal muscle and bone health. The vitamin D receptor (VDR) is present in muscle, as is CYP27B1, the enzyme that hydroxylates 25(OH)D to its active form, 1,25(OH)D. Furthermore, mounting evidence suggests that vitamin D may play an important role during muscle damage and regeneration. Muscle damage is characterized by compromised muscle fiber architecture, disruption of contractile protein integrity, and mitochondrial dysfunction. Muscle regeneration is a complex process that involves restoration of mitochondrial function and activation of satellite cells (SC), the resident skeletal muscle stem cells. VDR expression is strongly upregulated following injury, particularly in central nuclei and SCs in animal models of muscle injury. Mechanistic studies provide some insight into the possible role of vitamin D activity in injured muscle. In vitro and in vivo rodent studies show that vitamin D mitigates reactive oxygen species (ROS) production, augments antioxidant capacity, and prevents oxidative stress, a common antagonist in muscle damage. Additionally, VDR knockdown results in decreased mitochondrial oxidative capacity and ATP production, suggesting that vitamin D is crucial for mitochondrial oxidative phosphorylation capacity; an important driver of muscle regeneration. Vitamin D regulation of mitochondrial health may also have implications for SC activity and self-renewal capacity, which could further affect muscle regeneration. However, the optimal timing, form and dose of vitamin D, as well as the mechanism by which vitamin D contributes to maintenance and restoration of muscle strength following injury, have not been determined. More research is needed to determine mechanistic action of 1,25(OH)D on mitochondria and SCs, as well as how this action manifests following muscle injury in vivo. Moreover, standardization in vitamin D sufficiency cut-points, time-course study of the efficacy of vitamin D administration, and comparison of multiple analogs of vitamin D are necessary to elucidate the potential of vitamin D as a significant contributor to muscle regeneration following injury. Here we will review the contribution of vitamin D to skeletal muscle regeneration following injury.

Keywords: 25(OH)D; calcitriol; reactive oxygen species; satellite cells; skeletal muscle injury; skeletal muscle regeneration; vitamin D; vitamin D receptor.

Figure 1

Vitamin D status contributes to muscle damage and regeneration. Vitamin D deficiency leads to mitochondrial dysfunction, decreased adenosine triphosphate (ATP) production, increased reactive oxygen species (ROS) production, oxidative damage, muscle atrophy, and impaired muscle function. These symptoms of deficiency may exacerbate similar symptoms that typically occur with muscle damage (left panel). During muscle regeneration (right panel), hydroxylated, activated vitamin D [1,25(OH)D] stimulates an increase in vitamin D receptor (VDR) abundance in satellite cells and central myonuclei. These changes in VDR abundance are accompanied by inhibition of satellite cell proliferation and stimulation of differentiation, which may contribute to maintenance of satellite cell self-renewal capacity. Signaling at the VDR also increases mitochondrial biogenesis and fusion signaling, inhibit ROS production, and thereby mitigate antioxidant demand, which may contribute to a more competent regenerative phenotype. Created with BioRender.com

Figure 2

Localization of Vitamin D Receptor (VDR) in regenerating mouse and human skeletal muscle. (A,B) Muscle regeneration was induced in the mouse tibialis anterior muscle by injecting BaCl₂ (1.2%), and the tibialis anterior muscle was harvested 7 days following injury. Immunohistochemical analysis revealed regenerating fibers with centrally-located myonuclei (A, DAPI) show strong positive VDR expression (B, red puncta) in myonuclei. (C,D) A vastus lateralis biopsy was obtained from a human research participant 7 days after severe thermal injury, which we have shown to induce significant skeletal muscle regeneration (Fry et al. 2016). Myonuclear localization of VDR (D, red puncta) is observed, with the strongest VDR intensity present within myonuclei (C, DAPI) of small, regenerating fibers. In all images, laminin (green) denotes the fiber border. In images A and C, DAPI (blue) denotes nuclei. In images B and D, DAPI is omitted to allow visualization of VDR staining within nuclei. Scale bar = 100 μm.