Growth hormone secretagogues modulate inflammation and fibrosis in mdx mouse model of Duchenne muscular dystrophy
Résumé
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.
Mots clés
GHSR
hypothalamus
PVN
stress
CRF
HPA axis AgRP
agouti-related peptide ANOVA
analysis of variance ARH
hypothalamic arcuate nucleus AVP
vasopressin BW
body weight CSF
cerebrospinal fluid CRH
corticotropin-releasing hormone GABA
gamma-aminobutyric acid GAD2
glutamate decarboxylase 2 GFP
green fluorescent protein GHSR
growth hormone secretagogue
agouti-related peptide
ANOVA
analysis of variance
ARH
hypothalamic arcuate nucleus
AVP
vasopressin
BW
body weight
CSF
cerebrospinal fluid
CRH
corticotropin-releasing hormone
GABA
gamma-aminobutyric acid
GAD2
glutamate decarboxylase 2
GFP
green fluorescent protein
Duchenne muscular dystrophy mdx mouse growth hormone secretagogues skeletal muscle fibrosis
Duchenne muscular dystrophy
mdx mouse
growth hormone secretagogues
skeletal muscle
fibrosis
Domaines
Chimie thérapeutiqueOrigine | Publication financée par une institution |
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Licence |
Domaine public
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