Monday Muscle Seminar M&Ms: Hélène Duez Role of the circadian biological clock in muscle physiology
The biological clock has long been known to play crucial roles in several aspects of physiology, and clock disruption, as seen in shiftwork, frequent jetlag or extended light exposure and feeding period, increases the risk of developing a myriad of pathologies including metabolic and inflammatory disorders. Focusing on the clock component and drug targetable Rev-erbα nuclear receptor, our goal is to unravel the cellular and molecular mechanisms by which the clock impacts metabolism and inflammation in several patho-physiological contexts, particularly muscle diseases.
Le 23 nov. 2020
12:00 - 13:30
Conférence à distance
We reported that Rev-erb-α controls skeletal muscle mitochondrial biogenesis and oxidative function through enhanced Lkb1-Ampk-Sirt1-Pgc1α signaling. As a result, Rev-erbα deficiency led to decreased skeletal muscle mitochondrial content and aberrant morphology of the remaining mitochondrial network with increased autophagy, ultimately leading to compromised exercise capacity. Interestingly, pharmacological Rev-erb-α activation in skeletal muscle in vivo increases skeletal muscle mitochondrial respiration, energy expenditure and exercise capacity, identifying Rev-erb-α as a target to improve muscle function. In parallel, we studied muscle biopsies from healthy or obese/diabetic patients taken ‘around the clock’. Our results show that mitochondrial function oscillates throughout the 24h cycle in human myotubes, and that oscillations in clock genes are impaired when myotubes are isolated from diabetic patients. More recently, we showed that circadian misalignment in healthy young lean men compromises skeletal muscle insulin sensitivity, suggesting that impaired skeletal muscle clock function may contribute to the increased risk of type 2 diabetes observed in shiftworkers.
We also recently showed that Rev-erbα deficiency results in muscle mass loss and reduced fiber size. We found that administration of a Rev-erb agonist in the right time window is able to reverse dexamethasone-induced muscle atrophy, identifying Rev-erb-α as a promising target to limit muscle loss in patients with chronic inflammatory diseases treated with glucocorticoids. It remains to be determined whether Rev-erb-α activation is efficient at limiting muscle wasting in other contexts (eg. obesity/diabetes, cachexia, myopathy).
We are pursuing our research line by studying the role of Rev-erbα, and more generally of the clock, in sarcoplasmic reticulum homeostasis and calcium fluxes on one side, and in muscle regeneration after injury on the other. Our results point to a role of the clock in both muscle stem cells and infiltrating immune cells (ongoing).
Altogether these data identify the clock component Rev-erb-α as an interesting target for the treatment of muscle diseases.