Vitamin D Attenuates FOXO1-Target Atrophy Gene Expression in C2C12 Muscle Cells

Abstract

Summary Vitamin D is known to be effective for the prevention of muscle atrophy, such as age-related sarcopenia. However, vitamin D action in skeletal muscle tissue and muscle cells is largely unknown. We previously found that a transcription factor, FOXO1 gene expression, was induced in various muscle atrophy conditions causing muscle atrophy by upregulating atrophy-related genes, including atrogin 1 (ubiquitin ligase) and cathepsin L (lysosomal proteinase). In this study, we found that vitamin D inhibited FOXO1-mediated transcriptional activity in a reporter gene assay. Moreover, vitamin D suppressed the glucocorticoid-induced gene expression of atrogin 1 and cathepsin L in C2C12 myoblasts. Thus, vitamin D may prevent muscle atrophy via the FOXO1-mediated pathway in muscle cells. Key Words vitamin D, sarcopenia, atrophy, skeletal muscle, nuclear receptor Skeletal muscle is the largest organ in the human body, comprising approximately 40% of the total body weight, and it plays important roles in exercise, energy expenditure, and glucose/amino acid metabolism. Skeletal muscles plastically adapt to their environment, and appropriate exercise with sufficient nutrition increases muscle mass (1). Meanwhile, various life conditions, such as bedrest, aging, and other diseases, as well as a glucocorticoid treatment, cause muscle atrophy and decrease quality of life (2). In aging societies, which is a growing situation in many developed countries, the prevention/cure of atrophy is particularly important (1, 3). Understanding the molecular mechanisms underlying muscle hypertrophy/atrophy is important for developing methods to prevent muscle atrophy/dysfunction, which seriously impairs human health and quality of life.FOXO1 is a forkhead-type transcription factor that antagonizes insulin-mediated anabolic signals. We have been investigating the role of FOXO1 in metabolic regulation in skeletal muscles. Specifically, based on data that FOXO1 gene expression is induced by energy deprivation (4), we developed transgenic mice that overexpressed FOXO1 (FOXO1 Tg mice) and showed muscle atrophy (5). In addition, we showed that FOXO1 activates the genes involved in protein degradation (6, 7). FOXO1 activates the expression of atrophy-related genes such as atrogin 1 and cathepsin L in various muscle atrophyrelated conditions, including a glucocorticoid treatment (6-8). These findings suggest that FOXO1 in skeletal muscles plays an important role in muscle atrophy.Vitamin D, a fat-soluble vitamin, is well known for its role in regulating bone homeostasis. Evidence indicates that vitamin D plays roles in many other tissues including skeletal muscle (3,9). An epidemiological study suggested that a vitamin D treatment was effective for the prevention of decreased muscle mass (sarcopenia) (10). Previously, we first reported the cloning of mouse vitamin D receptor (VDR) cDNA (11). VDR is a nuclear receptor-type transcription factor, which is activated in the presence of 1,25(OH) 2 vitamin D3, the active form of vitamin D. It has been re...

Vitamin D and Sarcopenia: Potential of Vitamin D Supplementation in Sarcopenia Prevention and Treatment

“…A reporter assay system was prepared with the intention of measuring the transcriptional activity of FOXO1. After screening several compounds derived from various foods and plants, it was found that 1,25(OH) 2 D suppressed the transcriptional activity of FOXO1 [ 59 ]. Moreover, 1,25(OH) 2 D suppressed the increased expression of atrogin-1 and cathepsin L, target genes for FOXO1, which induces muscle atrophy in C2C12 myoblasts [ 59 ] ( Figure 2 ).…”

“…After screening several compounds derived from various foods and plants, it was found that 1,25(OH) 2 D suppressed the transcriptional activity of FOXO1 [ 59 ]. Moreover, 1,25(OH) 2 D suppressed the increased expression of atrogin-1 and cathepsin L, target genes for FOXO1, which induces muscle atrophy in C2C12 myoblasts [ 59 ] ( Figure 2 ). Interestingly, Yang et al recently reported that physical inactivity and low serum vitamin D can synergistically promote sarcopenia in the elderly [ 60 ].…”

Vitamin Intake and Loss of Muscle Mass in Older People with Type 2 Diabetes: A Prospective Study of the KAMOGAWA-DM Cohort

“…Low vitamin intake is reportedly related to the risk of frailty in older people [14]. In particular, the role of vitamin D, a fat-soluble vitamin, in sarcopenia has been increasingly reported [15][16][17]. Regulation of bone homeostasis is also the role of vitamin D [16].…”

“…In particular, the role of vitamin D, a fat-soluble vitamin, in sarcopenia has been increasingly reported [15][16][17]. Regulation of bone homeostasis is also the role of vitamin D [16]. An epidemiological study suggested that usage of vitamin D was effective for the prevention of decreased muscle mass [17].…”

“…Serum vitamin D level was associated with physical performance and frailty in cross-sectional studies [18,19], and coexisting low serum vitamin D level and high interleukin 6 level were associated with slow gait speed in a cross-sectional study [20]. Vitamin D was reported to suppress muscle atrophy through the suppression of forkhead box protein O1 (FOXO1) in skeletal muscle [16]. Moreover, it was reported that people with sarcopenia took lower vitamin B12 than people without [21].…”