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- Title
A new potential supportive role of MR409, a GHRH agonist, in an experimental mouse model of Spinal Muscular Atrophy.
- Authors
Boido, Marina; Gesmundo, Iacopo; Caretto, Anna; Schellino, Roberta; Schally, Andrew V.; Granata, Riccarda; Vercelli, Alessandro
- Abstract
Spinal Muscular Atrophy (SMA) is a pediatric neurodegenerative disease caused by the deletion or mutation of the telomeric gene "survival motor neuron 1" (SMN1), resulting in the loss of a-motor neurons (MNs) in the brainstem and in the spinal cord. Patients show a progressive skeletal muscular atrophy and neuromuscular junction (NMJ) defects, often leading to premature death. Nowadays, despite their effectiveness, SMN-dependent available therapies have different limitations (several adverse effects, high costs, unknown long-term effects and poor efficacy in milder patients or in late-treated people). Moreover, seen the demonstrated involvement of peripheral districts, new therapeutic approaches are emerging beside the SMNdependent treatments available. In this scenario, we have investigated the effects of MR409, a growth hormone-releasing hormone (GHRH) agonist that has already shown a remarkable activity in preventing apoptosis and proteolysis in an in vitro model of muscle atrophy (Gallo et al., 2015). To this aim, from postnatal day 2 (P2) to P12, we daily administered vehicle or MR409 (1mg/Kg and 2mg/Kg) to SMNdelta7 mice (a well-known murine model of SMA). We observed a progressive weight gain, especially with the highest dose, as well as significant improvements in motor behavior. These results positively correlated (in a dose-related manner) with histological and molecular analyses on quadriceps and gastrocnemius muscles, respectively early and late affected by the pathology. Indeed, H/E staining showed a significant increase in the size of the muscular fibers of MR409-treated mice. Moreover, immunofluorescence analyses on NMJs have shown a higher monoinnervation (sign of NMJ maturation) and a reduced denervation of the endplates. Additionally, molecular analyses revealed a significant enhancement in the expression of different isoforms of myosin heavy chains (MYH1, MYH2, MYH7 and MYH8) and of markers of myogenesis and muscular damage repairing (respectively, Myogenin and MyoD1), and a remarkable downregulation of MuRF1 and Atrogin-1 (whose increased expression seems correlated with muscular atrophy). Finally, by performing stereological counts of MNs in the lumbar spinal cord, we also observed a delay in cell death in the treated mice. Thus, our results suggest MR409 as a new promising therapeutic approach for the treatment of SMA, possibly in combination with SMN-dependent therapies.
- Subjects
SPINAL muscular atrophy; MUSCULAR atrophy; SPINAL cord; LABORATORY mice; WEIGHT gain; MOTOR neuron diseases
- Publication
Italian Journal of Anatomy & Embryology / Archivio Italiano di Anatomia Ed Embriologia, 2021, Vol 125, p30
- ISSN
1122-6714
- Publication type
Article