The Effect of Yearly-Dose Vitamin D Supplementation on Muscle Function in Mice

Abstract

Supplementation with vitamin D helps to alleviate weakness and fatigue seen with deficiency. However, large bolus doses appear to worsen the risk of falls. Whether this occurs as a direct result of muscle weakness is currently unknown. Thus, the aims of this study were to examine the muscle function following administration of high doses of vitamin D. Given the safety issues associated with bolus doses, experiments were conducted on C57BL6 mice. Mice at eight weeks of age with otherwise normal levels of vitamin D were supplemented for four weeks with a high dose (HIGH; n = 12) of vitamin D (20000 IU/kg food) designed to provide a year’s worth of vitamin D. These mice were compared to another group who received that same yearly dose in a single bolus i.p. injection (YEAR; n = 12). Mice provided with standard mouse chow, which contained 1000 IU/kg food, and injected with the vitamin D vehicle were used as controls (CON; n = 16). Force and fatigue properties of hind limb fast- and slow-twitch muscles were measured. CON animals ingested vitamin D consistent with typical human supplementation. HIGH animals consumed significantly more food than the CON animals, such that they ingested more than a year’s worth of vitamin D in four weeks. Despite this, there were few differences in the muscle function compared with CON. YEAR animals demonstrated lower absolute and relative forces in both muscles compared to the HIGH animals, as well as lower force during fatigue and early recovery. Large bolus doses of vitamin D appear to have detrimental effects on the skeletal muscle function, likely being a contributor to increased risk of falls observed with similar doses in humans. Mice ingesting the same amount over four weeks did not demonstrate the same deleterious effects, suggesting this may be a safe way to provide high vitamin D if required.

Vitamin D Supplementation and Impact on Skeletal Muscle Function in Cell and Animal Models and an Aging Population: What Do We Know So Far?

“…In another study, mice that were injected with a bolus 1500 IU of VitD3 had lower force in the extensor digitorum longus (EDL; fast-twitch) and soleus (slow-twitch) muscles when compared with higher levels of VitD3 (20,000 IU/kg food) for a longer period (9 weeks). These results confirm that different treatment strategies result in different outcomes, especially considering dose and duration [ 41 ]. Interestingly, VitD3 associated with a Mediterranean diet resulted in synergetic effect of muscle fibre hypertrophy when compared with regular diet with VitD3 only for 10 weeks in male rats [ 40 ] ( Table 2 ).…”

“…In addition, to that, our study also showed inconsistency to a meta-analysis of randomised controlled trials that evaluated the effects of VitD3 supplementation on muscle function and point out that it may be more beneficial to muscle strength if total serum [25(OH)D] at baseline was < 30 nmol/L [71]. Previous meta-analysis of trials concluded either a small beneficial effect (41,50) or no effect (51) of VitD3 supplementation on muscle mass or function.…”

Exercise May Ameliorate the Detrimental Side Effects of High Vitamin D Supplementation on Muscle Function in Mice

“…Even though these studies demonstrated rapid increases in serum 25(OH)D (inactive vitamin D) levels, these annual high doses have been found to be problematic, with reports of increased risk of falls and fracture . Although the mechanisms behind this effect are still unknown, skeletal muscle weakness, leading to increased tripping, has been suggested, and our recent study demonstrated a decrease in ex vivo muscle force production in mice receiving a single yearly dose …”

“…Evidence of improved calcium handling, findings of reduced muscle damage and improved recovery suggests that increasing vitamin D above sufficient levels may be of added benefit. However, as mentioned above, yearly injections of vitamin D, even in those that are vitamin D–deficient, have been associated with increased risk of falls potentially linked with muscle weakness, and similar yearly injections from a replete starting point, albeit in mice, reduced muscle force . However, this decline was not seen when the same amount was supplemented gradually through the diet.…”

“…(20,21) Although the mechanisms behind this effect are still unknown, skeletal muscle weakness, leading to increased tripping, has been suggested, and our recent study demonstrated a decrease in ex vivo muscle force production in mice receiving a single yearly dose. (22) Interestingly, despite potential deleterious effects of high supplementation, vitamin D status has been positively linked with various aspects of muscle function related to greater exercise performance. For example, it has been documented in numerous studies that serum 25(OH)D levels are positively correlated with muscle force and power, jump height, and aerobic capacity.…”