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

Abstract

Introduction:

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).

Methods:

Here, we aimed to provide preclinical evidence for potential benefits of GHSs in DMD, via a multidisciplinary in vivo and ex vivo comparison in mdx mice, of two ad hoc synthesized compounds (EP80317 and JMV2894), with a wide but different profile. 4-week-old mdx mice were treated for 8 weeks with EP80317 or JMV2894 (320 µg/kg/d, s.c.).

Results:

In vivo, 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%). Ex vivo, both drugs ameliorated DIA isometric force and calcium-related indices (e.g., 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 TGF-β1 and Col1a1. Also, decreased levels of pro-inflammatory genes (IL-6, CD68), accompanied by an increment in Sirt-1, PGC-1α and MEF2c expression, were observed in response to treatments, suggesting an overall improvement of myofiber metabolism. No detectable transcript levels of GHS receptor-1a, 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.

Discussion:

Our results support the interest of GHSs as modulators of pathology progression in mdx mice, disclosing a direct anti-fibrotic action that may prove beneficial to contrast pathological remodeling.

• Authors: Brigida Boccanegra, Ornella Cappellari, Paola Mantuano, Daniela Trisciuzzi, Antonietta Mele, Lisamaura Tulimiero, Michela De Bellis, Santa Cirmi, Francesca Sanarica, Alessandro Giovanni Cerchiara, Elena Conte, Ramona Meanti, Laura Rizzi, Elena Bresciani, Severine Denoyelle, Jean-Alain Fehrentz, Gabriele Cruciani, Orazio Nicolotti, Antonella Liantonio, Antonio Torsello, Annamaria De Luca
• Journal: Frontiers in immunology (Front Immunol) Vol. 14 Pg. 1119888 ( 2023) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 37122711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Boccanegra, Cappellari, Mantuano, Trisciuzzi, Mele, Tulimiero, De Bellis, Cirmi, Sanarica, Cerchiara, Conte, Meanti, Rizzi, Bresciani, Denoyelle, Fehrentz, Cruciani, Nicolotti, Liantonio, Torsello and De Luca.

Chemical References

• Growth Hormone
• Secretagogues
• Insulin-Like Growth Factor I

Topics

• Disease Models, Animal
• Inflammation (drug therapy, metabolism, pathology)
• Fibrosis
• Growth Hormone (pharmacology, therapeutic use)
• Muscular Dystrophy, Duchenne (metabolism, pathology)
• Secretagogues (metabolism)
• Mice, Inbred mdx
• Animals
• Mice
• Male
• Insulin-Like Growth Factor I (pharmacology, therapeutic use)