Cannabinoid-regulated autophagy as a target for studies involving cytoprotection and maturation of myoblasts obtained from induced pluripotent stem cell

• Grant number: 24/07361-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date until: October 01, 2024
• End date until: September 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Claudia Bincoletto Trindade
• Grantee: Lucas dos Santos Zamarioli
• Supervisor: Rita Perlingeiro Kyba
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: University of Minnesota (U of M), United States
• Associated to the scholarship: 21/14545-5 - Cannabinoid-regulated autophagy as a target for studies involving cytoprotection and maturation of myoblasts obtained from induced pluripotent stem cells, BP.DR

Abstract

Data in the literature demonstrate that autophagy is involved in the muscle proteolysis process. Recent work carried out by our group in collaboration with the University of Minnesota has really demonstrated a central role of autophagy in the process of muscle cell maturation obtained from induced pluripotent stem cells. This data is of particular importance, since the process of muscle mass loss is involved in several diseases, including cancer at an advanced stage. Thus, the establishment of in vitro models that can identify drugs that control the muscle proteolysis process is of great scientific interest, as there is a lack of data in the literature in this area. Thus, our objective in this project is to continue the project started in 2019 at the University of Minnesota, MN, USA, which involves the cell reprogramming of fibroblasts by the Sendai method, aiming to obtain myogenic progenitors from induced pluripotent stem cells for the in vitro identification of compounds with cytoprotective activity. In this project, we will study the pharmacological activity of cannabinoids (cannabidiol, cannabidivarin and ”8-tetrahydrocannabivarin), as there are data in the literature showing a possible cytoprotective effect of these compounds in several cell models, through the reestablishment of the autophagic response. However, studies involving cannabinoids in in vitro models of skeletal muscle are scarce. For this, myogenic progenitors subjected to cellular stress with muscle proteolysis inducing agents such as cardiotoxin, palmitate and conditioned medium of renal nephroma cells will be used in the evaluation of possible cytoprotective effects of cannabinoids via autophagy modulation. Proteolysis, cell death, signaling proteins, intracellular calcium mobilization, and expression of genes involved in muscle fiber maturation will be performed. This project intends to evaluate the in vivo actions of selected compounds in in vitro studies, which will be carried out through the BEPE at the University of Minnesota (U of M), MN, USA by administering the selected compounds in mdx animals deficient in dystrophin, which represent a model of Duchene muscular dystrophy (DMD), as well as the collaboration letter from Dr. Perlingeiro (responsible for the U of M experiments). In these animals, after treatment with cannabinoids, we will evaluate the size and number of myofibers, muscle contraction and collagen deposition. Thus, we will have in vitro data on the molecular effects of cannabinoids in muscle cell models and also data on their possible in vivo action, which makes the data robust and of great scientific interest in an area that lacks licensed drugs for the control of pathologies/injuries involving the skeletal musculature.