Mechanisms of vitamin D action in skeletal muscle – June 2019

Nutrition Research Reviews doi:10.1017/S0954422419000064
Karina Romeu Montenegro1, Vinicius Cruzat1,2, Rodrigo Carlessi1 and Philip Newsholme1
1School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA6102, Australia
2Faculty of Health, Torrens University Australia, Melbourne, VIC 3065, Australia

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Muscle tissue including cell

Note: Receptor appears 3 times in tissue and 2 times in cell

Chart Caption
Proposed mechanisms of action of vitamin D (VitD) in mammalian skeletal muscle cells. 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; AKT, serine–threonine kinase; Ca2þ, calcium ions; CREB, cellular transcription factor; c-Src, proto-oncogene c-Src; DAG, diacylglycerol; ELK1, ETS domain-containing protein; ERK1/2, extracellular signal-regulated kinases; HSP27, heat shock protein 27; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; OCR, oxygen consumption rate; P38, P38 mitogen-activated protein kinases; P70S6K, ribosomal protein S6 kinase β-1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol biphosphate; PKC, protein kinase C; PLCγ, phospholipase Cγ; Raf-1, proto-oncogene serine/threonine-protein kinase (also known as c-RAF); RNA poly, RNA polymerase; RXR, retinoid X receptor; SOCE, store-operated calcium entry; SR, sarcoplasmic reticulum; VDCC, L-type voltage-dependent calcium channel; VDR, vitamin D receptor; VDRE, vitamin D response elements.

Abstract
Vitamin D receptor expression and associated function have been reported in various muscle models, including C2C12, L6 cell lines and primary human skeletal muscle cells. It is believed that 1,25-hydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has a direct regulatory role in skeletal muscle function, where it participates in myogenesis, cell proliferation, differentiation, regulation of protein synthesis and mitochondrial metabolism through activation of various cellular signalling cascades, including the mitogen-activated protein kinase pathway(s). It has also been suggested that 1,25(OH)2D3 and its associated receptor have genomic targets, resulting in regulation of gene expression, as well as non-genomic functions that can alter cellular behaviour through binding and modification of targets not directly associated with transcriptional regulation. The molecular mechanisms of vitamin D signalling, however, have not been fully clarified. Vitamin D inadequacy or deficiency is associated with muscle fibre atrophy, increased risk of chronic musculoskeletal pain, sarcopenia and associated falls, and may also decrease RMR. The main purpose of the present review is to describe the molecular role of vitamin D in skeletal muscle tissue function and metabolism, specifically in relation to proliferation, differentiation and protein synthesis processes. In addition, the present review also includes discussion of possible genomic and non-genomic pathways of vitamin D action.

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