#apaperaday: The Adiponectin Receptor Agonist, ALY688: A Promising Therapeutic for Fibrosis in the Dystrophic Muscle

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: The Adiponectin Receptor Agonist, ALY688: A Promising Therapeutic for Fibrosis in the Dystrophic Muscle

Today’s pick is slightly older, from 2023 in @Dra_Cells by Dubuisson et al on testing an adiponectin receptor agonist in the mdx mouse model for Duchenne. Adiponectin is a growth factor produced by fat but also muscle. DOI: 10.3390/cells12162101

Adiponectin stimulates metabolism and has anti-inflammatory and oxidative metabolism enhancing activities. Overexpression of adiponectin in mdx mice improves regeneration and force and reduces inflammation. Knocking out adiponectin in mdx mice makes the pathology worse.

There are many different adiponectin isoforms, which makes treatment with adiponectin analogues challenging. Instead, authors use an agonist for the receptor (a molecule that triggers the receptor, like the adiponectin would do). This comound is ALY688

Authors here tested this in mdx mice at 3 and 15 mg/kg/day subcutaneous injection, compared to saline and a wild type group (hooray!). Authors do not mention whether they used males or males and females. Treatment had no effect on bodyweight, but improved wire hanging time????

Treatment improved strength & the distance mice were able to run on a treadmill. Only for wire hanging was there a dose dependent increase. for the other tests, the lowest dose appeared (almost) as effective. On histology treatment reduced inflammation similarly for each dose.

Authors also detected reduced levels of necrosis on H&E, but did not see a difference in the number of centrally located nuclei. They did see an increase in revertant fibers, which they explained as an indirect effect of improved regeneration.

Markers for regeneration were indeed increased on RNA level. Fibrosis was reduced – for none of these approaches there was a dose effect seen. Also did different analyses on different skeletal muscles, but did not analyze the most severely affects mdx muscle, the diaphragm ????

Authors did confirm the mechanism of action, i.e. the stimulation of the AdipoReceptor, as AMPK signaling was induced. They finally showed in cultured cells that the ALY-688 stimulating effect and AMPK signaling was inhibited when AdipoReceptor 1 was downregulated.

Authors discuss that ALY-688 is a slow release agonist, which allow less frequent dosing. They also outline that this compound acts on different pathways: reducing inflammation and stimulating regeneration – just like HDAC inhibition.

Like me they were surprised by the lack of a dose effect. They suggest the compound may act with a bell-shaped curve, i.e. there is an optimum and dosing more, will reduce the effect. If this is the case, more studies are needed to find which dose is the optimal dose.

Finally authors suggest this may be an alternative to steroids – however, they did not do a head to head comparison, so that conclusion is a bit premature. Also, I would be interested to see what the combination of ALY-688 and steroids does: is there an additive effect or now?

So more work is needed as usual, but I appreciate authors used wild type references and did a lot of different analyses. Would have been really interesting to see the effect size of treatment on the diaphragm, as the skeletal muscle pathology is limited.