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

Authors :
Boccanegra B
Cappellari O
Mantuano P
Trisciuzzi D
Mele A
Tulimiero L
De Bellis M
Cirmi S
Sanarica F
Cerchiara AG
Conte E
Meanti R
Rizzi L
Bresciani E
Denoyelle S
Fehrentz JA
Cruciani G
Nicolotti O
Liantonio A
Torsello A
De Luca A
Source :
Frontiers in immunology [Front Immunol] 2023 Apr 12; Vol. 14, pp. 1119888. Date of Electronic Publication: 2023 Apr 12 (Print Publication: 2023).
Publication Year :
2023

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).<br />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.).<br />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.<br />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.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (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.)

Details

Language :
English
ISSN :
1664-3224
Volume :
14
Database :
MEDLINE
Journal :
Frontiers in immunology
Publication Type :
Academic Journal
Accession number :
37122711
Full Text :
https://doi.org/10.3389/fimmu.2023.1119888