BACKGROUND: Adiponectin has been shown to protect damaged muscle tissue from incurring additional injury resulting from excessive local inflammation, oxidative stress, and pro-fibrotic response. Adiponectin levels are reduced in DMD patients. In the mdx mouse model, lack of adiponectin exacerbated muscle injury while replacement reduced muscle damage. Administration of recombinant adiponectin protein is challenging due to its large size and high production costs. ALY688 is a small (10 aa) engineered adiponectin peptide mimetic that drives the same signaling pathways as adiponectin.
OBJECTIVE: To better understand the activity of ALY688 as a potential disease-modifying therapy for DMD, ALY688 was studied in mdx mice to assess its effects on the dystrophic phenotype and to elucidate its mechanisms-of-action.
RESULTS: Young (4 wk) and aged (56 wk) male C57BL/10ScSn-DmdmdxJ mdx mice were treated with ALY688 SC QD for 8 and 12 weeks, respectively. Compared with vehicle-treated mdx mice, ALY688 improved physical performance in both young and aged mice. In young mdx mice, ALY688 (15 mg/kg) treatment improved hang time by +67% vs. mdx-vehicle (p<0.001), while in aged mice, ALY688 (10 mg/kg) showed a +50% change from baseline vs +12% in mdx-vehicle (p<0.05). To better understand the underlying mechanisms by which ALY688 improved muscle function, muscle tissue was examined for markers of necrosis, inflammation, and fibrosis. Compared with mdx-vehicle mice, ALY688 treated mice showed significantly reduced myonecrosis, inflammatory cytokine expression, oxidative stress markers, CD68+ macrophages, and fibrotic response (collagen, TGF-b). Interestingly, ALY688-treated animals also showed an increase in dystrophin-positive revertant myofibres and markers of differentiation, providing evidence for a positive effect on the myogenic program. Like adiponectin, ALY688 treatment activated key effectors of the AMPK-PGC-1a axis, decreasing NF-kB activity and upregulating utrophin expression.
CONCLUSIONS: In both young and aged mdx mice, ALY688 improved muscle function through multiple complementary mechanisms, including inhibition of myonecrosis, inflammation, and fibrosis, as well as enhancement of myogenesis and differentiation. ALY688 shows promise as a novel therapy for DMD to improve muscle function and delay disease progression by reducing the damaging effects of chronic muscle inflammation and fibrosis.