Ablation of satellite cell-specific clock gene, Bmal1, alters force production, muscle damage, and repair following contractile-induced injury

Abstract

Following injury, skeletal muscle undergoes repair via satellite cell (SC)-mediated myogenic progression. In SCs, the circadian molecular clock gene, Bmal1, is necessary for appropriate myogenic progression and repair with evidence that muscle molecular clocks can also affect force production. Utilizing a mouse model allowing for inducible depletion of Bmal1 within SCs, we determined contractile function, SC myogenic progression and muscle damage and repair following eccentric contractile-induced injury. At baseline, SC-Bmal1^iKO animals exhibited a ~20-25% reduction in normalized force production (ex vivo and in vivo) versus control SC-Bmal1^Cntrl and SC-Bmal1^iKO untreated littermates (p < .05). Following contractile injury, SC-Bmal1^iKO animals displayed reduced muscle damage and subsequent repair post-injury (Dystrophin^negative fibers 24 h: SC-Bmal1^Cntrl 199 ± 41; SC-Bmal1^iKO 36 ± 13, p < .05) (eMHC⁺ fibers 7 day: SC-Bmal1^Cntrl 217.8 ± 115.5; SC-Bmal1^iKO 27.8 ± 17.3; Centralized nuclei 7 day: SC-Bmal1^Cntrl 160.7 ± 70.5; SC-Bmal1^iKO 46.2 ± 15.7). SC-Bmal1^iKO animals also showed reduced neutrophil infiltration, consistent with less injury (Neutrophil content 24 h: SC-Bmal1^Cntrl 2.4 ± 0.4; SC-Bmal1^iKO 0.4 ± 0.2, % area fraction, p < .05). SC-Bmal1^iKO animals had greater SC activation/proliferation at an earlier timepoint (p < .05) and an unexplained increase in activation 7 days post injury. Collectively, these data suggest SC-Bmal1 plays a regulatory role in force production, influencing the magnitude of muscle damage/repair, with an altered SC myogenic progression following contractile-induced muscle injury.

Keywords: contractile injury; force production; molecular clocks; muscle repair; muscle stem cells; myogenic progression.