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Growth hormone secretagogues modulate inflammation and fibrosis in mdx mouse model of Duchenne muscular dystrophy.
- 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
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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.)
- Subjects :
- Disease Models, Animal
Inflammation drug therapy
Inflammation metabolism
Inflammation pathology
Fibrosis
Mice, Inbred mdx
Animals
Mice
Male
Growth Hormone pharmacology
Growth Hormone therapeutic use
Muscular Dystrophy, Duchenne metabolism
Muscular Dystrophy, Duchenne pathology
Secretagogues metabolism
Insulin-Like Growth Factor I pharmacology
Insulin-Like Growth Factor I therapeutic use
Subjects
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