“Growth hormone secretagogues (GHSs) may represent a therapeutic opportunity for Duchenne muscular dystrophy (DMD), due to their wide pharmacological profile and ability to contrast damaging signals in other muscle-wasting conditions. Clinically relevant effects of GHSs in DMD need to be assessed via preclinical investigations. Two GHSs (EP80317 and JMV2894) were beneficial in terms of functional recovery and control of muscle inflammation and fibrosis in classic mdx mice. Docking studies disclosed a potential binding ability of JMV2894 on metalloproteases ADAMTS-5 and MMP-9, overactivated in DMD. So, we tested JMV2894 in D2.B10-Dmdmdx/J (D2-mdx) mouse model, characterized by a severe profibrotic genetic background.
4-weeks-old D2-mdx mice were treated with JMV2894 at two doses (640 and 1280 µg/kg/d, s.c.) for 6 weeks. In vivo, JMV2894 induced a partial, dose-dependent improvement of hind limb plantar flexor torque in D2-mdx mice. This was accompanied by a decrease in gastrocnemius (GC) muscle ultrasound echodensity and an increase in hind limb volume with the lower dose. Diaphragm (DIA) echodensity was also partly reduced, while DIA respiratory movement amplitude was ameliorated.
However, DIA muscle force ex vivo was not improved. Histological analyses showed no reduction of unhealthy tissue or fibrosis. The lower dose induced a reduction of calcifications in D2-mdx mice’s hearts.
Molecular biology assessments revealed a decrease in the expression of profibrotic, atrophy and inflammation markers. PK analyses showed a limited drug exposure in muscle tissue.
Our results confirm the interest in GHSs in dystrophic settings and support the need to develop novel formulations to optimize their bioavailability. [AFM-Téléthon Grant #22199].”