Review
The effects of vitamin D on skeletal muscle function and cellular signaling

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Abstract

It is thought that every cell in the body expresses the vitamin D receptor, and therefore vitamin D may play a role in health and homeostasis of every organ system, including skeletal muscle. Human, animal, and cell culture studies have collectively shown that vitamin D affects muscle strength and function. Vitamin D functions in a plethora of cellular processes in skeletal muscle including calcium homeostasis, cell proliferation, cell differentiation, fiber size, prevention of fatty degeneration, protection against insulin resistance and arachidonic acid mobilization. These processes appear to be mediated by several signaling pathways affected by vitamin D. This review aims to explore the effects of vitamin D on skeletal muscle in each model system and to delineate potential cell signaling pathways affected by vitamin D.

Highlights

► Effects of vitamin D (Vit D) in human, animal, and cell culture models are reviewed. ► Vit D affects strength, balance, atrophy, and fatty degeneration shown in humans. ► Animal studies show that Vit D is important for skeletal muscle growth and homeostasis. ► Vit D affects Ca homeostasis, proliferation, differentiation, and insulin resistance. ► These processes are mediated through genomic and non-genomic mechanisms.

Introduction

The role of vitamin D in health and disease has been a popular topic in the medical literature and popular news for two reasons. First, the prevalence of vitamin D deficiency and insufficiency is much more wide spread than once thought. Vitamin D insufficiency has been defined as 25(OH)D concentrations between 20 and 30 ng/ml, while concentrations below 20 ng/ml are considered deficient [1]. In the United States 70% of children, ranging in age from 1 to 21 years, were found to be vitamin D deficient or insufficient [2]. In adults the prevalence may be up to 73% and in the elderly nearly up to 78% [3]. Shown in the Third National Health and Nutrition Examination Survey 2001–2004, African American and Mexican American individuals had lower mean serum concentrations compared to white individuals [4]. Ethnic groups with darker skin require proportionally more sun exposure to synthesize equivalent amounts of vitamin D compared with people with lighter skin [5]. Obese individuals also have a higher risk of vitamin D insufficiency or deficiency compared to non-obese; likely due to decreased bioavailability of vitamin D caused by its sequestration in cutaneous fat depots [6]. Other contributing factors behind the wide spread vitamin D insufficiency or deficiency include inadequate vitamin D in the diet, lack of sun exposure, and genetic factors [7]. A recent study has identified common gene variants that increase the risk for vitamin D deficiency [7]. Hence, the majority of the U.S. population may have sub-optimal concentrations of vitamin D that are potentially impacting health.

Secondly, it has come to light that vitamin D has much more of a global role in health and disease of numerous organ systems than once realized. Scientists and physicians are revealing that the physiological role of vitamin D is quite expansive beyond its classical role in calcium homeostasis and skeletal health. For example, vitamin D has been shown to reduce the risk of various cancers, hypertension, heart disease, infectious diseases, multiple sclerosis, rheumatoid arthritis, asthma, and depression [8], [9], [10], [11], [12], [13]. Furthermore, low vitamin D concentrations have been implicated in the development of type I diabetes as well as insulin insensitivity and type II diabetes [14]. Vitamin D status may also be linked to body weight. It has been shown that insufficient vitamin D can stunt growth and increase body weight, body mass index, and abdominal fat during puberty [15]. Further, vitamin D has been associated with the aging process. It has been shown that premature aging occurs in vitamin D receptor mutant mice [16]. Women with higher concentrations of vitamin D had longer leukocyte telomeres, which is a sign of being biologically younger and healthier [17]. While much attention in the medical literature has been given to the effects of vitamin D on the skeletal system, cardiovascular system, and its role in preventing various cancers, much less attention has focused on the effects of vitamin D on skeletal muscle, which is the focus of this review. Current research has shown that vitamin D has beneficial actions that lead to enhanced muscle strength, function, and performance. The purpose of this review is to discuss the effects of vitamin D on skeletal muscle in human subjects, animal models, and cell culture models and to delineate potential signaling pathways affected by vitamin D.

Section snippets

Metabolism of vitamin D

Activation of vitamin D involves multiple organs (see Fig. 1). Vitamin D2 or D3, derived from plants or conversion of 7-dehydrocholesterol in the skin by ultraviolet B radiation of mammals respectively, is hydroxylated in the liver to 25-hydroxyvitamin D [25(OH)D] by vitamin D-25-hydroxylase. 25(OH)D is the major circulating form of vitamin D in the blood, although, this form is inactive and must be converted in the kidneys to the biologically active form, 1,25 hydroxyvitamin D [1,25-(OH)2D3]

Human studies: the effects of vitamin D on skeletal muscle function and performance

Until recently, studies involving vitamin D and human subjects have focused on its role in bone health and its impact on calcium homeostasis. However, it has become clear that vitamin D affects muscle function through the binding of 1,25-(OH)2D3 to VDR, resulting in muscle growth as well as other adaptations [23], [24]. The effect of vitamin D on skeletal muscle suggests that its relationship to muscle strength may influence the prevalence of falls in the elderly. Poor muscle strength and

Animal studies: the effects of vitamin D on skeletal muscle

Animal studies exploring the role of vitamin D on skeletal muscle have predominantly used the VDR knockout mouse known as the VDR null mutant mouse. The VDR null mutant mouse is characterized by hair loss [64], a reduction in body weight, and a reduction in body size [64], [65], [66]. Loss of the VDR also causes a shorter gait and impaired motor coordination [64], [65], [66]. Furthermore, these animals show abnormal swimming ability as illustrated by vertical swimming and sinking which suggests

Cell culture studies: cellular effects of vitamin D on muscle cells

Early on it was shown that both myoblasts and myotubes express 1,25-(OH)2D3 receptor(s) and showed no differences in the quantity or characteristics of the receptor(s) between the two cells [71]. Specifically, it was shown that cloned human myoblasts and fused myotubes exhibited similar specific binding data between 1,25-(OH)2D3 and its receptor(s); both cells responded with a dose-dependent increase in 25-hydroxyvitamin D3-24-hydroxylase enzyme activity after treatment with 1,25-(OH)2D3 [71].

Conclusion

The health benefits of vitamin D are widespread, and it is becoming evident that they may involve most, if not all, of the organ systems. Vitamin D insufficiency and/or deficiency are prevalent and reach individuals of all ages. Recently discovered, various gene variants may contribute to the vitamin D insufficiency and/or deficiency that seem to be a pandemic and therefore, may be contributing to various disease states. In skeletal muscle, it has become clear that vitamin D is important for

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