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

Cells. 2023 Aug 19;12(16):2101. doi: 10.3390/cells12162101.

Abstract

Duchenne muscular dystrophy (DMD) is one of the most devastating myopathies, where severe inflammation exacerbates disease progression. Previously, we demonstrated that adiponectin (ApN), a hormone with powerful pleiotropic effects, can efficiently improve the dystrophic phenotype. However, its practical therapeutic application is limited. In this study, we investigated ALY688, a small peptide ApN receptor agonist, as a potential novel treatment for DMD. Four-week-old mdx mice were subcutaneously treated for two months with ALY688 and then compared to untreated mdx and wild-type mice. In vivo and ex vivo tests were performed to assess muscle function and pathophysiology. Additionally, in vitro tests were conducted on human DMD myotubes. Our results showed that ALY688 significantly improved the physical performance of mice and exerted potent anti-inflammatory, anti-oxidative and anti-fibrotic actions on the dystrophic muscle. Additionally, ALY688 hampered myonecrosis, partly mediated by necroptosis, and enhanced the myogenic program. Some of these effects were also recapitulated in human DMD myotubes. ALY688's protective and beneficial properties were mainly mediated by the AMPK-PGC-1α axis, which led to suppression of NF-κβ and TGF-β. Our results demonstrate that an ApN mimic may be a promising and effective therapeutic prospect for a better management of DMD.

Keywords: ALY688; AMPK; adiponectin; duchenne muscular dystrophy; fibrosis; inflammation; myonecrosis; necroptosis; regeneration; skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin*
  • Animals
  • Fibrosis
  • Humans
  • Mice
  • Mice, Inbred mdx
  • Muscle Fibers, Skeletal
  • Receptors, Adiponectin*

Substances

  • Adiponectin
  • Receptors, Adiponectin

Grants and funding

This study was funded by a research contract agreement with Allysta Pharmaceuticals Inc. This work was also supported by grants from the Belgian Telethon (ABMM), the French Association against Myopathies (AFM Téléthon) and the Fund for Scientific Research—FNRS (PDR/T.0026.21). MAS is Chargé de Recherches and ND Spécialiste Doctorant at the FNRS. CMS has received a fellowship from the FRIA.