Growth hormone secretagogues modulate inflammation and fibrosis in mdx mouse model of Duchenne muscular dystrophy

• Published in: Frontiers in immunology Vol. 14; p. 1119888
• Main Authors: Boccanegra, Brigida, Cappellari, Ornella, Mantuano, Paola, Trisciuzzi, Daniela, Mele, Antonietta, Tulimiero, Lisamaura, De Bellis, Michela, Cirmi, Santa, Sanarica, Francesca, Cerchiara, Alessandro Giovanni, Conte, Elena, Meanti, Ramona, Rizzi, Laura, Bresciani, Elena, Denoyelle, Severine, Fehrentz, Jean-Alain, Cruciani, Gabriele, Nicolotti, Orazio, Liantonio, Antonella, Torsello, Antonio, De Luca, Annamaria
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers 2023; Frontiers Media S.A
• Subjects: Animals; Chemical Sciences; Disease Models, Animal; Duchenne muscular dystrophy; Fibrosis; Growth Hormone - pharmacology; Growth Hormone - therapeutic use; growth hormone secretagogues; Human health and pathology; Immunology; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor I - therapeutic use; Life Sciences; Male; mdx mouse; Medicinal Chemistry; Mice; Mice, Inbred mdx; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - pathology; Pharmaceutical sciences; Pharmacology; Secretagogues - metabolism; skeletal muscle; fibrosis; growth hormone secretagogues; skeletal muscle; mdx mouse; Duchenne muscular dystrophy
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1119888

Growth hormone secretagogues (GHSs) exert multiple actions, being able to activate GHS-receptor 1a, control inflammation and metabolism, to enhance GH/insulin-like growth factor-1 (IGF-1)-mediated myogenesis, and to inhibit angiotensin-converting enzyme. These mechanisms are of interest for potentially targeting multiple steps of pathogenic cascade in Duchenne muscular dystrophy (DMD). Here, we aimed to provide preclinical evidence for potential benefits of GHSs in DMD, a multidisciplinary and comparison in mice, of two synthesized compounds (EP80317 and JMV2894), with a wide but different profile. 4-week-old mice were treated for 8 weeks with EP80317 or JMV2894 (320 µg/kg/d, s.c.). , both GHSs increased mice forelimb force (recovery score, RS towards WT: 20% for EP80317 and 32% for JMV2894 at week 8). In parallel, GHSs also reduced diaphragm (DIA) and gastrocnemius (GC) ultrasound echodensity, a fibrosis-related parameter (RS: ranging between 26% and 75%). , both drugs ameliorated DIA isometric force and calcium-related indices ( , RS: 40% for tetanic force). Histological analysis highlighted a relevant reduction of fibrosis in GC and DIA muscles of treated mice, paralleled by a decrease in gene expression of and . Also, decreased levels of pro-inflammatory genes ( ), accompanied by an increment in and expression, were observed in response to treatments, suggesting an overall improvement of myofiber metabolism. No detectable transcript levels of , nor an increase of circulating IGF-1 were found, suggesting the presence of a novel receptor-independent mechanism in skeletal muscle. Preliminary docking studies revealed a potential binding capability of JMV2894 on metalloproteases involved in extracellular matrix remodeling and cytokine production, such as ADAMTS-5 and MMP-9, overactivated in DMD. Our results support the interest of GHSs as modulators of pathology progression in mice, disclosing a direct anti-fibrotic action that may prove beneficial to contrast pathological remodeling.