Endocrinology November 1, 2013 vol. 154 no. 11 3963-3964
Centre Hospitalier Universitaire de Caen, Department of Genetics, Reference Center for Rare Disorders of Calcium and Phosphorus Metabolism Caen, F-14000, France; UCBN, Caen, F-14032; and Institut National de la Santé et de la Recherché Médicale, U1075, Caen, F-14032, France
Address all correspondence and requests for reprints to: Marie-Laure Kottler M.D., Ph.D., Head Centre Hospitalier Universitaire de Caen Genetics, Avenue Georges Clemenceau, Caen, France F-14033. E-mail: kottler-ml at chu-caen.fr.
Historically, vitamin D is viewed as fundamental to bone mineralization. However, it is well established that muscle strength and muscle mass are important determinants of bone density, bone geometry, and fracture risk. Vitamin D therefore plays a key role in bone metabolism not only through its direct effects on osteoblasts, calcium absorption by the intestines, but also through its effects on muscle fiber size and muscle function (1,–,3).
Vitamin D may influence muscle physical function in 2 ways:
- indirectly through calcium-related effects and
- directly via its role in muscle cell regulation.
On a cellular level, a variety of mechanisms by which vitamin D impacts upon the function of skeletal muscle have been elucidated. These can be broadly divided into genomic effects that arise from the binding of the nuclear receptor (NR) (vitamin D receptor [VDR]), and nongenomic effects.
In its biologically active form 1,25(OH)2 D binds to VDR, which is a ligand-dependent nuclear transcription factor (4). VDR is heterodimerized with retinoid X receptor (RXR) and the complex activates positive vitamin D response element genes transcription. This increases synthesis of proteins related to several pathways in muscle functions, including Ca2+-binding proteins, such as calmodulin and calbindin D-9K. It also results in an increase in synthesis of other muscle cytoskeletal proteins important for muscle function and trophicity, namely IGF-binding protein-3, thereby inducing muscle hypertrophy. However, in some tissues, RXR levels are greater than VDR levels (5). Therefore, changes in VDR levels are rate limiting for VDR/RXR-mediated target gene expression. Coimmunoprecipitation analyses have also demonstrated direct binding of VDR with c-src under the influence of 1,25(OH)2 D, which mediates the stimulation of muscle growth and differentiation by its subsequent effects on MAPK-signaling pathways (6).
Cellular 1,25(OH)2 D also elicits fast-acting responses that cannot be explained by activation of the slow nuclear VDR genomic pathway that requires hours for protein synthesis. This response is believed to be mediated by the activation of a plasma membrane-associated VDR that stimulates several interacting second-messenger pathways that transmit the signal to the cytoplasm (7). However, a cross talk between 1,25(OH)2 D activation of the plasma-membrane-bound VDR and the nuclear VDR action can exist.
Both types affect Ca2+ handling and muscle cell proliferation and differentiation.
The presence of VDR in muscle has been reported on the basis of immunohistochemistry and detection of VDR mRNA by RT-PCR (7), but these results are subject to challenge due to the experimental conditions (8). Differences in the expression of VDR through the various stages of muscle differentiation may have accounted for these discrepancies.
Deletion of VDR in mice (VDR knockout [KO] mouse model) has provided valuable insights into the biologic function of the vitamin D endocrine system. VDRKO mice present with abnormal skeletal muscle development and deregulated expression of myoregulatory transcription factors (9). These mice display atrophy of type I and II muscle fibers. These changes were observed in VDRKO mice on high-calcium diet, suggesting that the absence of VDR was the predominant cause rather than systemic biochemical changes.
A positive association between vitamin D status and muscle function has been observed in rodent models or in humans.
Vitamin D deficiency impairs excitation-contraction coupling in skeletal muscle leading to impairment in muscle-force generation. In a rat model, a decrease in sarcoplasmic reticulum that impairs the rate of Ca2+ uptake as well as the amount of Ca2+ release in response to an action potential has been described. Expression of myogenic factors was down-regulated, suggesting a decrease in muscle mass.
In humans, muscle weakness in vitamin D-deficient individuals is often described, and biopsies of skeletal muscle in adults show similar type II (fast twitch) muscle fiber atrophy (2).
The precise mechanisms by which vitamin D impairs muscle differentiation, fiber size, and muscle function are unclear.
The paper published in this issue of Endocrinology by Bhat and colleagues (14) is thus an important contribution to this field.
The authors used a vitamin D-deficient rat model supplemented with either calcium or vitamin D to examine whether muscle wasting is due to an increased protein degradation or a decreased protein synthesis or both. They studied the 3 different proteolytic pathways described in the skeletal muscle, namely the ATP-dependent ubiquitin proteasome pathway (UPP), the lysosomal pathway, and the calpaïn pathway.
Substantial observations over the past 5 years support the notion that the ubiquitin–proteasome system plays a role in NR-mediated transcriptional regulation at least through the traditional role in proteolysis of NR and NR cofactor complexes (10). Accordingly, VDR is degraded by the UPP. Elegant studies have shown that vitamin D stabilizes its NR and inhibits degradation by the 26S proteasome (11, 12).
Degradation of cellular proteins via the UPP is a highly complex and tightly regulated process. Proteins targeted for degradation by the 26S proteasome are tagged by ubiquitin moieties with the help of a cascade of 3 enzymes, namely E1, E2, and E3 (10).
In this paper, the authors showed that muscle wasting in vitamin D-deficient rats is due to increased muscle protein breakdown despite food intake similar to vitamin D-sufficient rats. They found an increase of muscle atrophy markers while the expression of the proteasome subunit genes such as the 20S catalytic unit of the 26S proteasome and E2-ubiquitin-conjugating enzyme, was increased. The coordinated up-regulation of enzyme activities, gene and protein expression of various components of the UPP, suggests a major role for vitamin D in this pathway.
These changes were reversed by vitamin D rehabilitation and partially corrected by calcium alone.
The expression of lysosomal enzymes genes and calpaïn enzyme genes was not affected, suggesting that the UPP was the major pathway involved in muscle protein degradation in vitamin D deficiency.
In fasting and presumably in other disease states, muscles play an important role in providing the organism with precursors for hepatic gluconeogenesis or for new protein synthesis. In atrophying rat skeletal muscles, inhibitors of the proteasome reduce the accelerated proteolysis (13).
The data presented in this paper suggest that vitamin D could have a function in preventing proteolysis to mobilize amino acids from dispensable muscle proteins.
Thus, in addition to its role in calcium homeostasis, vitamin D could be an important factor in the balance between protein synthesis and degradation that determines whether muscles hypertrophy or atrophy.
The better understanding of mechanisms of vitamin D action in muscle highlights the significance of maintaining optimal levels of vitamin D and calcium for good muscle health.
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10. Glickman MH, Ciechanover A . The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373–428. Abstract/FREE Full Text
11. Peleg S, Nguyen CV . The importance of nuclear import in protection of the vitamin D receptor from polyubiquitination and proteasome-mediated degradation. J Cell Biochem. 2010;110:926–934.
12. Li XY, Boudjelal M, Xiao JH, et al . 1,25-Dihydroxyvitamin D3 increases nuclear vitamin D3 receptors by blocking ubiquitin/proteasome-mediated degradation in human skin. Mol Endocrinol. 1999;13:1686–1694. Abstract/FREE Full Text
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14. Bhat, Kalam R, SYH Qadri S, Madabushi S, Ismail A . Vitamin D Deficiency-Induced Muscle Wasting Occurs through the Ubiquitin Proteasome Pathway and Is Partially Corrected by Calcium in Male Rats. Endocrinology. 2013;154:4018–4029.
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