Background: Although the role of vitamin D receptor (VDR) in muscle mass and strength is well established, the effects of vitamin D (VD) on muscle remain controversial due to various factors. Herein, the influence of sex on the effects of VD on muscle function and the underlying reasons was explored. Methods: Male and female Sod1 gene knockout (SKO) mice, serving as a model for skeletal muscle atrophy, were treated with the VD active analogue calcipotriol, and RNA sequencing was employed to investigate this potential signalling pathway. The National Health and Nutrition Examination Survey (NHANES) database was utilized to explore whether testosterone affects the correlation between VD and grip strength in human participants. Experiments involving C2C12 cells and castrated male mice subjected to immobilization were conducted to demonstrate the enhancing effects of testosterone on VD function. Results: In male SKO mice, Vdr expression in the gastrocnemius muscle was positively correlated with grip strength ( R ² = 0.4689, p < 0.001), whereas no such correlation was identified in female mice. At 28 weeks of age, both male and female SKO mice exhibited significantly reduced grip strength compared to Sod1 wild‐type (SWT) mice, and calcipotriol restored grip strength in male SKO mice (SWT‐veh: 0.0716 ± 0.0006, SWT‐cal: 0.0686 ± 0.0010, SKO‐veh: 0.0601 ± 0.0010, SKO‐cal: 0.0703 ± 0.0007; p < 0.05). Calcipotriol increased muscle protein synthesis and mitochondrial biogenesis while decreasing inflammation and atrogenes in gastrocnemius muscle of male SKO mice. However, the effect of calcipotriol on muscle was not significant in female SKO mice. Compared to wild‐type mice, both male and female SKO mice exhibited reduced levels of 1,25(OH) ₂ D ₃ due to ROS‐induced hepatic CYP3A4 overexpression, thereby excluding the influence of baseline VD levels. The serum 25(OH)D ₃ and testosterone interactively affect grip strength in adults ( p < 0.05). Using C2C12 cells differentiated into myotubes, testosterone significantly enhanced the inducing effects of VD on VDR, androgen receptor (AR), P‐AKT, PGC1α, Beclin1 and LC3B. Calcipotriol improved grip strength in sham‐operated mice but had a negligible effect on grip strength in castrated mice. However, a significant improvement in grip strength was observed in castrated mice following testosterone restoration ( p < 0.05). Conclusions: This study demonstrates the existence of sex heterogeneity in the effects of VD on muscle and that testosterone enhances the strength and molecular responses to VD. These findings underscore the importance of considering testosterone levels when utilizing VD to enhance muscle strength.

In a lean NAFLD mouse model, vitamin D ₃ accentuated hepatic steatosis, while calcipotriol diminished inflammation; the reason may be their selective activation of VDR in hepatocytes and liver macrophages, respectively.

Background/Objectives: As a hyperaccumulator of selenium (Se), Cardamine violifolia (Cv) and its peptide extract could ameliorate the negative effects of a high-fat diet (HFD). However, the effects of the coaccumulation of cadmium (Cd) in Se-enriched Cv (Cv2) and the potential confounding effect on the roles of enriched Se remain unknown. We aimed to investigate whether Cv2 could alleviate HFD-induced lipid disorder and liver damage. Methods: Three groups of 31-week-old female mice were fed for 41 weeks (n = 10–12) with a control Cv-supplemented diet (Cv1D, 0.15 mg Se/kg, 30 µg Cd/kg, and 10% fat calories), a control Cv-supplemented HFD (Cv1HFD, 45% fat calories), and a Cv2-supplemented HFD (Cv2HFD, 1.5 mg Se/kg, 0.29 mg Cd/kg, and 45% fat calories). Liver and serum were collected to determine the element concentrations, markers of liver injury and lipid disorder, and mRNA and/or protein expression of lipid metabolism factors, heavy metal detoxification factors, and selenoproteins. Results: Both Cv1HFD and Cv2HFD induced obesity, and Cv2HFD downregulated Selenoi and upregulated Dio3 compared with Cv1D. When comparing Cv2HFD against Cv1HFD, Cv2 increased the liver Se and Cd, the protein abundance of Selenoh, and the mRNA abundance of 10 selenoproteins; reduced the serum TG, TC, and AST; reduced the liver TG, lipid droplets, malondialdehyde, and mRNA abundance of Mtf1 and Mt2; and differentially regulated the mRNA levels of lipid metabolism factors. Conclusions: Cv2 alleviated HFD-induced lipid dysregulation and liver damage, which was probably associated with its unique Se speciation. However, further research is needed to explore the interaction of plant-coenriched Se and Cd and its effects on health.

This study utilizing Selenoh gene knockout mice identified that Selenoh mediates low selenium-related cognitive decline in female mice, an effect attributed to impaired oligodendrocyte myelination with disrupted lipid metabolism in the hippocampus.

The association between heavy metal exposure and diabetes is controversial and vitamin E (VE) may reduce diabetes risk. We aimed to examine the associations between blood heavy metals (BHMs) and diabetes risk and VE’s role in the relationship. From the 2007–2018 NHANES, 10,721 participants aged ≥ 18 were included for multiple statistical analyses, which revealed that BHMs and dietary VE intake were negatively associated with diabetes and fasting plasma glucose (FPG). The diabetes prevalence in each quartile (Q) of heavy metal exposure increased with age, but within age Q4, it generally decreased with exposure quartiles. Moreover, BHMs were positively associated with all-cause and diabetes-related mortalities with aging, which induced an age breakpoint of 65 years for age-stratified analyses on the associations between BHMs and diabetes risk. In those aged > 65, BHMs were negatively correlated with diabetes risk and its biomarkers; however, in adults aged 18–65, the correlation was positive. At higher VE intake levels, blood lead was associated with a lower diabetes risk and all three BHMs demonstrated lower FPG levels than those at lower VE intake levels. In conclusion, consuming sufficient VE and avoiding heavy metal exposure are highly recommended to reduce diabetes risk.