More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORa
Circadian rhythms, governed by the dominant central as well as various peripheral clocks, regulate almost all biological processes, including sleep-wake cycles, hormone secretion, and metabolism. In certain contexts, regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle-intrinsic clock-dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period 2 (Per2) and RAR-related orphan receptor alpha (RORa), respectively.  In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem involved in the homeostasis of amine groups. Very divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the Per2, and non-oscillating genes in the RORa knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity, and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determine a finely tuned adaptation of muscle tissue to perturbations in health and disease. Overall design: Muscles from PER2 muscle-specific knockout mice (MKO), control (CTRL), and RORa MKO mice were collected at zeitgeber time (ZT) 0, 4, 8, 12, 16, and 20. 3-4 mice were used for seqeuencing replicated for each time-point and each genotype.