#apaperaday: Muscle mitochondrial remodeling by intermittent glucocorticoid drugs requires an intact circadian clock and muscle PGC1α

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Muscle mitochondrial remodeling by intermittent glucocorticoid drugs requires an intact circadian clock and muscle PGC1α.

Today’s pick is from Science Advances by Quattrocelli et al on the timing of corticosteroids and effects on muscle strength and function. All work in healthy mice. Well conducted basic research from McNally group. Doi10.1126/sciadv.abm1189

Glucocorticosteroids are expressed in a pattern, with a peak dose present just before you normally wake (which is why you feel so rotten if you have to wake up really early and why you often wake up at work get-up time on the weekend).

Many patients are treated with glucocorticosteroids like prednisone, including Duchenne patients. Since steroids follow this circadian rhythm pattern, authors wondered whether there was a difference in muscle response based on when external steroids were delivered in healthy mice

They treated 12 week old mice for 12 weeks with weekly prednisone treatment either at the start of their light phase or dark phase (NB mice are awake during the dark phase). When prednisone was given at the start of the light phase, this resulted in positive effects in muscle:

The oxidative capacity, endurance and strength were improved as was muscle mass. This did not happen when prednisone was given at the start of the dark phase. BMAL1 is a protein that is important in regulating the resting phase in non CNS tissues (such as muscle).

When authors did the prednisone experiment in mice lacking BMAL1 they did not see a beneficial muscle effect. Authors then did chromatine IP experiments in both wild type and BMAL1 knockout mice with and without prednisone treatment.

Multiple signals confirm experiment was properly done (e.g. glucocorticoid response elements –> genes known to be activated by steroids were activated by prednisone treatment in muscle of wild type mice – but less in BMAL knockout mice).

Two genes were selected for further study: Nampt and Ppargc1alpha (PGC1a)(both involved in energy production and mitochondrial capacity). Prednisone pulses showed increased expressions of both when prednisone was delivered at the start of light phase but not at start of dark phase.

Authors generated a local inducible PGC1a knockout mouse in muscle. In quadriceps this reduced PGC1a levels by 85% and this reduced the positive effects on muscle function and energy production after prednisone treatment at the start of the light phase.

This is all very interesting, but what does it mean for Duchenne patients, who chronically use corticosteroids as well. This is currently unknown but the authors stress that for now the results are in mice and validation in humans is not yet available.

Note that mice sleep during the day, while we sleep during the night – interestingly the way this is regulated by the biological clock is similar. My own additional considerations: many Duchenne patients use daily steroids or intermittent daily steroids, study uses weekly

Furthermore, steroids in Duchenne patients do more than improving energy production – they also act as antiinflammatory drugs and they likely ‘reset’ the disrupted patterns of de- and regeneration. So more work is needed to study if and what this means for Duchenne.

Finally, authors discuss that for Duchenne, vamorolone is being developed as well. The question is if this also has effects related to the timing of taking the compound. This deserves further studies as well. I hope these studies will be performed.

If you can have a better effect of a drug when taking it in the morning or evening that is of course a very easy way to improve efficacy. However, for now there is no indication this is the case in humans, and more specifically for regular steroid use. To be continued hopefully.

 

Pictures by Annemieke, used with permission.