Review
Vitamin D and skeletal muscle tissue and function

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Abstract

This review aims to summarize current knowledge on the role of vitamin D in skeletal muscle tissue and function. Vitamin D deficiency can cause a myopathy of varying severity. Clinical studies have indicated that vitamin D status is positively associated with muscle strength and physical performance and inversely associated with risk of falling. Vitamin D supplementation has shown to improve tests of muscle function, reduce falls, and possibly impact on muscle fiber composition and morphology in vitamin D deficient older adults. Molecular mechanisms of vitamin D action on muscle tissue include genomic and non-genomic effects via a receptor present in muscle cells. Genomic effects are initiated by binding of 1,25-dihydroxyvitamin D [1,25(OH)2D] to its nuclear receptor, which results in changes in gene transcription of mRNA and subsequent protein synthesis. Non-genomic effects of vitamin D are rapid and mediated through a cell surface receptor. Knockout mouse models of the vitamin D receptor provide insight into understanding the direct effects of vitamin D on muscle tissue. Recently, VDR polymorphisms have been described to affect muscle function. Parathyroid hormone which is strongly linked with vitamin D status also may play a role in muscle function; however, distinguishing its role from that of vitamin D has yet to be fully clarified. Despite the enormous advances in recent decades, further research is needed to fully characterize the exact underlying mechanisms of vitamin D action on muscle tissue and to understand how these cellular changes translate into clinical improvements in physical performance.

Introduction

It has been well-established that vitamin D plays an essential role in the regulation of calcium and phosphate homeostasis and in bone development and maintenance (DeLuca, 2004). Classically, vitamin D is known to exert its actions on target organs, such as the intestine, the kidney, the parathyroid glands, and bone. Over the last two decades, however, there has been increasing evidence that vitamin D plays an important role in many other tissues including skeletal muscle. Early clinical descriptions of a reversible myopathy associated with vitamin D deficiency and/or chronic renal failure recognized a potential association between vitamin D and muscle (Boland, 1986). The identification of the vitamin D receptor (VDR) on muscle cells (Zanello et al., 1997, Bischoff et al., 2001) provided further support for a direct effect of vitamin D on muscle tissue. Recent investigations in cell culture and animals have advanced our understanding of some of the molecular mechanisms through which vitamin D targets skeletal muscle; however, much remains to be characterized. This review summarizes the clinical evidence of an association between vitamin D status and muscle function, describes how vitamin D affects muscle tissue morphology, considers the molecular mechanisms of vitamin D activity in normal muscle tissue, outlines the lessons learned from the VDR knockout mouse model, discusses potential VDR polymorphisms and their relationship to muscle function, and touches on parathyroid hormone’s (PTH) effects on muscle.

Section snippets

Vitamin D deficient myopathy

The first associations between vitamin D and muscle function were made from clinical observations of muscle weakness in osteomalacia from vitamin D deficiency. In infants this myopathy is classically characterized by muscle weakness and hypotonia (Prineas et al., 1965). In adults it may present as predominantly proximal muscle weakness with difficulty in walking up stairs, in rising from a sitting or squatting position, and in lifting objects. However, the muscle weakness can present without

Vitamin D deficiency and muscle histology

Muscle biopsies in adults with profound vitamin D deficiency have shown predominantly type II muscle fiber atrophy. Of note, type II muscle fibers are fast-twitch and are the first to be recruited to prevent a fall. Thus, the fact that primarily type II fibers are affected by vitamin D deficiency may help explain the falling tendency of vitamin D deficient elderly individuals (Snijder et al., 2006). Histological sections of vitamin D deficient individuals also reveal enlarged interfibrillar

VDR in muscle tissue

The biologically active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], exerts its principal actions by binding to a vitamin D receptor (VDR).

VDRs are expressed in muscle tissue at particular stages of differentiation from myoblasts (mononucleated myogenic cells) to myotubes (multinucleated cells). In 1985, Simpson et al. identified a binding protein consistent with the 1,25(OH)2D receptor in rodent skeletal muscle cell lines (Simpson et al., 1985). At the same time, other reports

Studies in VDR knockout mouse model

The VDR knockout mouse model has provided strong evidence for a direct effect of vitamin D and its receptor on skeletal muscle tissue. VDR null mutant mice are characterized by alopecia, reductions in both body size and weight and impaired motor coordination (Burne et al., 2005). Another feature of the VDR knockout behavioral phenotype is poor swimming ability (as assessed by the forced swimming test) (Kalueff et al., 2004). Studies in VDR null mutant mice show that they grow normally until

VDR polymorphisms and muscle strength

Several VDR polymorphisms, which are defined as subtle variations in DNA sequence of the VDR gene, exist that are associated with a range of biological characteristics including muscle strength. For example, one well-described polymorphism, FokI, is a polymorphism involving a T/C transition in exon 2 of the VDR gene (Hopkinson et al., 2008). Individuals with the C allele (“F”) have a shorter 424-amino acid VDR than do those with the T (“f”) allele, the former having been associated with

PTH effects on muscle

Clinically, patients with PTH excess (as in hyperparathyroidism) share similar symptoms of muscle weakness and fatigue (Kristoffersson et al., 1992) and muscle biopsies demonstrate atrophy of type II muscle fibers as in vitamin D deficiency (Patten et al., 1974). Furthermore, PTH has been shown to predict falls (Stein et al., 1999) and muscle strength independent of 25(OH)D, age, and BMI (Dhesi et al., 2002). The question of whether vitamin D deficiency itself or secondary hyperparathyroidism

Conclusion

The link between vitamin D and skeletal muscle health has been well-described in clinical studies. There is a broad range of muscle dysfunction associated with varying degrees of vitamin D insufficiency, and supplementation with various forms of vitamin D has mostly shown beneficial effects. The identification of the VDR in skeletal muscle tissue provides solid evidence for a direct role of the vitamin. Recent research studies in the last two decades have begun to identify genomic effects of

Disclosure Statement

The author has nothing to disclose.

This material is based upon work supported by the US Department of Agriculture, Agricultural Research Service, under agreement No. 58-1950-7-707. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the US Department of Agriculture.

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