Novel insights into the effects of JMV2894, a growth hormone secretagogue, in Duchenne muscular dystrophy: A preclinical study in the D2-mdx mouse model

Growth hormone secretagogues (GHSs) are gaining interest as promising therapeutics for Duchenne muscular dystrophy (DMD) due to their broad activity profile and proven benefits in other muscle-wasting conditions. We previously found that JMV2894 - a pseudopeptide GHS - exerts functional, anti-inflammatory, and antifibrotic benefits in classic BL10-mdx mice, supported by in silico predictions of its interaction with ADAMTS-5 and matrix metalloproteinase 9 (MMP-9), both overactivated in DMD. This led us to test JMV2894 in the D2.B10-Dmd^mdx/J (D2-mdx) mouse model, chosen for its hyper-fibrotic and atrophic disease phenotype. JMV2894 was administered subcutaneously at 640 or 1280 µg/kg for six weeks to 4-week-old D2-mdx mice, showing good tolerability. In vivo, the treatment partially improved hind limb plantar flexor torque, ultrasound volume, and reduced gastrocnemius (GC) muscle echodensity. While decreasing the expression of matrix-remodeling genes (i.e., MMP-9, ADAMTS-5, transforming growth factor beta-1, type I collagen α1), JMV2894 only mildly alleviated GC muscle fibrosis histologically. However, JMV2894 - particularly at the lower dose - exerted a remarkable anti-atrophic action, evidenced by increased GC myofiber size and decreased gene expression of Atrogin and Muscle RING Finger 1. Enhanced insulin-like growth factor 1 (IGF-1) transcript and plasma levels, along with increased IGF-1 receptor and downstream signalling proteins, suggest that JMV2894 actions are most likely GH-mediated. These effects occurred despite limited muscle drug exposure, highlighting the need for improved formulations to enhance bioavailability. Overall, our results show that GHSs exert different actions in dystrophic settings, likely related to distinct disease phenotype, reflecting the complexity of translational exercise towards universal therapies in DMD.