Vitamin D, Muscle Function, and Falls in Older Adults: Does Reduced Deposition of Intramuscular Adipose Tissue Influence the Relationship?

Abstract

In addition to its established role in bone and mineral homeostasis, there is growing evidence for a role of vitamin D in skeletal muscle physiology. Vitamin D deficiency has long been implicated in muscle function. Observational studies report an increase in muscle weakness and falls in vitamin D deficiency. Clinical trials also suggest that vitamin D supplementation may improve muscle strength and balance and reduce risk of falls in those with vitamin D deficiency; however, there is controversy regarding these effects because the current evidence base is restricted by highly heterogeneous studies (1). Vitamin D deficiency may be associated with preferential atrophy of type II muscle fibers, and this potentially explains the association of vitamin D with reduced strength and increased risk of falls. However, vitamin Dassociated improvements in skeletal muscle function are unlikely to be explained by muscle hypertrophy alone. For example, we have previously reported that spanning almost 3 years in a population-based study of older adults, higher baseline serum 25-hydroxyvitamin D (25OHD) was associated with improved maintenance of lower-limb strength but not appendicular lean mass assessed by dualenergy x-ray absorptiometry (2). If vitamin D exerts a direct effect on human skeletal muscle, it follows that vitamin D receptors (VDRs) should be located in the skeletal muscle. Research has indicated that 1,25-dihydroxyvitamin D3 (1,25OH2D3) binds to a nuclear receptor in muscle and promotes de novo protein synthesis, and in support of this, VDR-knockout mice exhibit reduced muscle fiber size and poor vestibular function. Studies using several different antibodies have reported that the VDR is expressed in adult muscle tissue, but this is currently controversial; the VDR was reported to be undetectable in normal and mature mouse, rat, and human skeletal muscle tissue using a highly sensitive and specific VDR antibody (3). The present questions surrounding the VDR are whether the VDR is indeed expressed in skeletal muscle in vivo and whether it exists in fully differentiated adult muscle or only in immature muscle cells as suggested by in vitro studies (1). A recent Endocrine Society Scientific Statement has concluded that there is controversy regarding the role of vitamin D in skeletal muscle function but that there is evidence that effects of vitamin D on muscle function may be both direct and indirect. The statement suggests that the effects of vitaminDonmuscle functionmaybeexplainedbyvitamin D-related changes in calcium absorption, as reported by Ebeling et al (4), rather than a direct interaction with skeletal muscle VDR (3). We propose there may be an additional mechanism through which vitamin D exerts an indirect effect, which may be unrelated to a skeletal muscle VDR; reductions in intraand intermuscular adipose tissue (IMAT) deposition. A characteristic of aging skeletal muscle is increased deposition of adipose tissue within and between muscle fibers, and IMAT appears to have independent and deleterious outcomes for skeletal muscle function. It has been proposed that IMAT may contribute to declines in muscle function by altering the orientation and hence force production capabilities of skeletal muscle and by secreting inflammatory cytokines leading to systemic low-level inflammation that has been associated with reduced force production (5). Observational studies have reported an association between IMAT and functional decline in older adults. Among well-functioning participants of the U.S. Health, Aging and Body Composition study, IMAT at the