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#apaperaday: Update on anti-fibrotic pharmacotherapies in skeletal muscle disease

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Update on anti-fibrotic pharmacotherapies in skeletal muscle disease

Pick is from Current Opinion in Pharmacology by Muraine et al on anti-fibrotic strategies for skeletal muscle diseases. DOI: 10.1016/j.coph.2022.102332

Fibrosis is an excess accumulation of extracellular matrix components. Fibrosis can occur in many tissues, but the focus here is on skeletal muscle, where fibrosis is the result of impaired muscle repair after (often chronic) damage. Muscle repair normally is a stepwise approach: inflammation to clear damage, activation of satellite cells to make/repair the muscle fiber and fibro-adipogenic progenitors (FAP) to make new connective tissue around the fiber.

When there is chronic damage these processes are misaligned and FAPs will make too much extracellular matrix and muscle stem cells too little muscle. Once this happens, the excess fibrosis will maintain this process by stimulating FAPs & inhibiting myoblasts/satellite cell repair.

There are many factors that play a role in this switch from normal muscle repair to failed muscle repair and fibrosis. As such there are many different inroads for anti-fibrotic therapies. Authors outline multiple options. For more detail I refer to the 3 page long table!

Here are some highlights: TGF-beta is my one but least favorite protein (after NFkB) and is a master regulator of fibrotic processes. Inhibiting it seems a logical choice, but the challenge is that TGF-beta plays a role in many other processes and the risk of unintended things is large.

From personal experience: because of its importance, there are many parallel routes so down regulation often leads to compensation & no downstream effects. Also, timing matters, down regulation at the right time (which then is the wrong time for other muscle and non target tissue)

Authors therefore suggest targeting downstream targets to have more specific and controlled effects. e.g. targeting the phosphorylation of SMAD3 or the receptor of TGFbeta (Activin IIB + ALK4 to avoid off target effects of activin y& BMP signaling that also goes via Activin IIB). Other options are targeting less central transcription factors such as CTGF (connective tissue growth factor), or targeting tissue remodeling enzymes (MMPs), or the renin-angiotensin system (RAS).

Finally inflammation can be inhibited, as chronic inflammation and accompanying oxidative stress also play a role in fibrosis. N-acetyl cysteine (see this paper a day)  features as well! Many compounds have been studied, but so far none has been found effective in clinical trials.

Authors mention givinostat, the HDAC inhibitor targeting multiple processes: increasing repair and inhibiting fibrosis and inflammation. I think the reason the givinostat phase 3 trial in Duchenne met its primary endpoint is because it targets multiple aspects rather than just one.

authors indeed conclude that ideally multiple pathways are targeted, but also that the compounds are selective rather than general. Connective tissue has important functions in the body so you only want to target the excess production.

Authors also stress that to test the compounds it is important to use the proper animal models. This is of course in line with my own mantra 🙂 Match your model system to your research question so you get clear and robust answers. Nice review!