Circadian rhythms are responsible for various rhythmic 24-hour changes in physiological and behavioral parameters. A core oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for the coordination of these rhythms. The SCN controls the endogenous timing system by coordinating the tissue-specific clocks present in all cells of the body. The regulation is mainly based on a core transcriptional-translational feedback loop that keeps internal gene expression entrained by the external light-dark cycle. The transcription factor Bmal1 is a major component of both central and peripheral clocks, and its absence leads to disruption of circadian rhythms.
In order to understand the function of the intrinsic muscle clock we compared two muscle specific knockouts of the Bmal1 gene (a conditional model Bmal1 mKO and an inducible model Bmal1 imKO) and their normal wild type littermates. Changes in muscle phenotype were analyzed at morphological and physiological level, and muscle gene expression was determined.
We have observed that in contrast with the whole body Bmal1 knockout, Bmal1 mKO mice have a normal lifespan and growth. Contrary to the extreme muscle atrophy found in Bmal1 null mice, muscle-specific Bmal1 mKO causes a small but significant increase in muscle mass. However, this hypertrophic phenotype is not accompanied by an increase in muscle force, and indeed there is a marked reduction in both absolute muscle force and muscle force normalized to muscle weight. Myofibrillar architecture is conserved in Bmal1 mKO muscles, and there are no major histological abnormalities in the muscles. Myosin heavy chain composition is slightly shifted to fast myosin heavy chain isoforms. We have compared the muscle circadian gene expression profile of these mice and their control littermates. Our analyses indicate that the transcription of many circadian muscle genes is greatly altered. By Gene Set Enrichment Analysis (GSEA) we found that the p38 pathway, including upstream activators and downstream targets, is down−regulated, suggesting that this pathway, which is known to be linked to contractile activity, is controlled by BMAL1
