Agonist of growth hormone-releasing hormone improves the disease features of spinal muscular atrophy mice

Author:

Boido Marina1ORCID,Gesmundo Iacopo2ORCID,Caretto Anna1,Pedrolli Francesca2ORCID,Schellino Roberta1,Leone Sheila3ORCID,Cai Renzhi45,Sha Wei4,Ghigo Ezio2,Schally Andrew V.45678ORCID,Vercelli Alessandro1ORCID,Granata Riccarda2ORCID

Affiliation:

1. Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Turin, Italy

2. Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy

3. Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy

4. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125

5. South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL 33125

6. Divisions of Medical/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136

7. Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136

8. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136

Abstract

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene ( SMN1 ). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.

Funder

Ministero dell'Università e della Ricerca

Ministero dell'Istruzione, dell'Università e della Ricerca

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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