ReviewVitamin D and skeletal muscle tissue and function
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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