The Journal of Steroid Biochemistry and Molecular Biology
ReviewThe effects of vitamin D on skeletal muscle function and cellular signaling
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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