Biomedicines · 5 authors, 3 centres
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In a rat model of blunt soleus muscle injury, systemic calcitriol treatment significantly improved incomplete tetanic force recovery and myofiber width by day 14 compared to control, while VDRM2 showed intermediate effects. Calcitriol also increased cell proliferation and reduced apoptosis on day 4 post-injury. These findings suggest calcitriol may enhance muscle regeneration after trauma, though VDRM2 had lower biological activity.
**Background:** Muscle injuries are common in sports and trauma, often leading to functional deficits. Vitamin D (calcitriol) has pleiotropic effects that may enhance muscle regeneration by increasing cellular turnover and reducing apoptosis. Non-secosteroidal vitamin D receptor modulators (VDRMs), such as VDRM2 (LSN2148936), are synthetic ligands that activate similar pathways but may avoid hypercalcemic side effects. This study compared the effects of calcitriol and VDRM2 on muscle recovery after blunt injury in rats.
**Methods:** Sixty-eight male Wistar rats (355 ± 36 g) underwent a standardized open blunt contusion of the left soleus muscle (7 × 10 s at 25 N). Animals were randomly assigned to three groups: control (10% ethanol i.p., n=21), calcitriol (1 μg/kg/day i.p., n=21), or VDRM2 (1 μg/kg/day i.p., n=21), with injections on days 0–3 post-injury. On days 1, 4, and 14 (n=7 per group per time point), in vivo muscle force was measured via direct stimulation of the soleus muscle at 9 mA/75 Hz for incomplete tetanic (0.1 s) and complete tetanic (3 s) contractions. Histological and immunohistochemical analyses included BrdU labeling for proliferation, TUNEL for apoptosis, CAE staining for myeloid cell infiltration, and HE staining for myofiber width and muscle tissue fraction. Statistical analysis used one-way ANOVA or ANOVA on ranks with p<0.05 considered significant.
**Key Results:** All animals survived without complications. Muscle force declined substantially after injury in all groups. On day 14, the calcitriol group showed significantly higher incomplete tetanic force compared to control (36% decline vs. 52% decline in control; p<0.05), while VDRM2 showed a 37% decline (not significantly different from control). Complete tetanic force showed similar trends but did not reach statistical significance. Proliferation (BrdU+ cells/mm²) was significantly elevated in both calcitriol and VDRM2 groups on day 4 compared to control (p<0.05), with no differences on days 1 or 14. Apoptosis (TUNEL+ cells/mm²) peaked on day 4 in all groups; calcitriol significantly reduced apoptosis on day 4 versus control (p<0.05), while VDRM2 showed intermediate values. CAE-positive cell counts were not significantly different among groups at any time point. Myofiber width on day 14 was significantly greater in the calcitriol group compared to control and VDRM2 (p<0.05). Muscle tissue fraction increased over time in all groups, reaching approximately 56.2% by day 14, with no significant intergroup differences.
**Clinical Implications:** This study provides evidence that systemic calcitriol administration after muscle injury enhances functional recovery, increases cellular proliferation, reduces apoptosis, and improves myofiber width in a rat model. VDRM2 showed only modest effects on proliferation and no significant improvement in muscle force or structure. These findings suggest that calcitriol may be a promising therapeutic agent for promoting muscle regeneration after trauma, though VDRM2 appears less effective. The results are not directly translatable to humans without further research, but they support the potential of vitamin D-based interventions in sports medicine and trauma surgery. The tissue-specific actions of VDRM2 warrant additional investigation to clarify its mechanism and optimal dosing.