8:30am - 8:50amInvestigating a new therapeutic role of the GHRH agonist MR-409 in an experimental model of Spinal Muscular Atrophy
Marina Boido1, Iacopo Gesmundo2, Anna Caretto1, Francesca Pedrolli2, Roberta Schellino1, Sheila Leone3, Renzhi Cai4,5, Wei Sha4, Ezio Ghigo2, Andrew V. Schally4,5,6,7,8, Alessandro Vercelli1, Riccarda Granata2
1Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Italy; 2Department of Medical Sciences, University of Turin, Italy; 3Department of Pharmacy, G. d’Annunzio University, Chieti, Italy; 4Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA; 5South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL, USA; 6Divisions of Medical/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA; 7Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA; 8Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
Spinal muscular atrophy (SMA) is a severe neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene (SMN1) and consequent reduced levels of SMN protein. SMA is characterized by the degeneration of lower motor neurons (MNs), associated with muscle atrophy, as well as other peripheral alterations.
Here we investigated the efficacy of the growth hormone-releasing hormone (GHRH) agonist MR-409 that in other experimental models has been able to exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation.
We evaluated the protective role of MR-409 in SMNdelta7 mice, a widely used murine model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to P12, increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy in quadriceps and gastrocnemius muscles, as demonstrated by the increased expression of several myosin heavy chain isoforms (Myh1, Myh2, Myh7 and Myh8) and of markers of myogenesis and muscular damage repairing (Myog and Myod1), as well as by a significant downregulation of apoptosis markers correlated with muscular atrophy (MuRF1 and Atrogin-1). 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 MN death and blunted neuroinflammation in the spinal cord of SMA mice.
In conclusion, our results demonstrated that MR-409 is a new promising therapeutic approach for the treatment of SMA, possibly in combination with the available SMN-dependent therapies.
8:50am - 9:10amMuscle and motor neurons as partners in crime in ALS. Cellular and molecular mechanisms of muscle-nerve interplay.
Antonio Musarò
Sapienza University of Rome, Italy
The functional interplay between muscle and nerve is crucial for both partners to survive and function adequately throughout the life. A crucial system severely affected in several neuromuscular diseases is the loss of effective connection between muscle and nerve, leading to a pathological non-communication between the two tissues. One of the best examples of impaired interplay between the nerve and muscle is observed in ALS. ALS is a disorder involving degeneration of motor neurons, muscle atrophy and paralysis. The heterogeneity of the disease and failures in developing satisfactory therapeutic protocols reinforce the view that ALS is a multi-factorial and multi-systemic pathology. Whereas the steps leading to the pathological state are well characterized, several fundamental issues are still controversial: are the motor neurons the first and only targets of ALS? What is the contribution of muscle, if any, to the pathogenesis of ALS?
In the presentation, we will present and discuss data related to:
i) the retrograde-talk muscle-to-nerve,
ii) the evidence on how and to what degree muscle plays a role in the progression of the pathology (from passive bystanders to active players in ALS pathophysiology),
iii) the molecular mechanisms involved in the dialogue between the different cell types,
iv) potential therapeutic approaches based on the “saving-back” process.
9:10am - 9:30amDefective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle
Caterina Marchioretti
University of Padua
Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes.
9:30am - 9:45amEnergy dysmetabolism in amyotrophic lateral sclerosis: a role for peroxisomes
Martina Terricola1,2, Rachel Price1,2, Silvia Scaricamazza3, Illari Salvatori3, Stefano Giuliani1, Cristian Fiorucci1, Manuela Cervelli1,2, Francesco Berardinelli1,2, Alberto Ferri3, Cristiana Valle3, Sandra Moreno1,2
1Department of science, University Roma TRE, Italy; 2Lab of Neurodevelopmental, Neurogenetics and Molecular Neurobiology, IRCCS Fondazione S. Lucia, Rome, Italy; 3Lab of Neurochemistry, IRCCS Fondazione S. Lucia, Rome, Italy
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons, leading to paralysis. Energy dysmetabolism and oxidative stress, related to mitochondrial impairment, have been recognized in ALS patients and contribute to disease progression. A contribution to energy dysmetabolism is also given by skeletal muscle, which determines a derangement of basal metabolic rate, switching its metabolism towards an oxidative phenotype and to the preferential use of fatty acids as fuel1.
Based on the role of peroxisomes in energy metabolism and on their crosstalk with mitochondria, the aim of this study is to address peroxisomal involvement in ALS. Indeed, peroxisomes and mitochondria exhibit a functional cooperation in multiple metabolic and signaling networks, such as lipid (e.g., fatty acids β-oxidation) and reactive oxygen species (ROS) metabolism. This suggests that mitochondrial alterations can influence peroxisomal functions, and vice versa2.
Peroxisomes are dynamic organelles whose anabolic and catabolic functions can adjust to a changing environment, under control of peroxisome proliferator activated receptors (PPARs), a subfamily of transcription factors. PPAR action depends upon binding to their ligands and is regulated by coactivators as PGC1α3.
In this study we performed immunoblotting and qRT-PCR analyses to assess the expression of peroxisomal markers in the gastrocnemius muscle and spinal cord of SOD1G93A transgenic mouse at 70 and 120 days of age. The results obtained show a significant increase of peroxisomal fatty acyl β-oxidation enzymes (thiolase and acyl-CoA oxidase 1), peroxisome membrane protein of 70kDa (PMP70) and antioxidant enzymes (catalase and superoxide dismutase 2), in both tissues at the symptomatic stage. Such up-regulation is accompanied by PPARα induction. These data support an involvement of peroxisomes in ALS, which deserves further attention.
- Scaricamazza et al. 2021 Cells 10:525.
- Wahli & Michalik 2012 TEM 23:351.
- Islinger et al. 2018 Histochem Cell Biol 150:443.
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