Beta2-adrenoceptor plays a key role in skeletal muscle physiology/morphology. Its activation improves skeletal muscle function/mass and therefore counteracts muscle weakness/wasting seen in several degenerative conditions including cancer, sepsis and cardiovascular diseases. However, the molecular mechanisms involved in these processes are still elusive. Here we plan to study the role of Beta2-adrenoceptor in regulating skeletal muscle protein quality control (PQC) in a rat model of muscle disuse induced by a permanent sciatic nerve constriction. The cellular PQC machinery, mainly driven by ubiquitin-proteasome system and autophagy, monitors and protects long lived-cells against accumulation of cytotoxic proteins by detecting and properly disposing them. Our preliminary results demonstrate that skeletal muscle weakness/wasting is associated with impaired skeletal muscle PQC, depicted by accumulation of misfolded, ubiquitinated and carbonylated proteins during muscle disuse. Of interest, sustained Beta2-adrenoceptor activation using Formoterol (10 ¼g/kg/day) increase both proteasomal (50%) and lysosomal (90%) activities during skeletal muscle disuse. These changes are followed by reduction of cytotoxic protein levels (80%) and better skeletal muscle contractility (450%). Additionally, sustained autophagy inhibition using Chloroquine (50 mg/kg/day) over 14 days, but not proteasomal inhibition (Bortezomib, 0.2 mg/kg/day), is sufficient to abolish in vivo Beta2-adrenoceptor agonist effects on skeletal muscle PQC, mass and strength. These preliminary findings suggest that autophagy, but not proteasomal-mediated proteolysis, is a limiting factor of Beta2-adrenoceptor effects on skeletal muscle. Therefore, we decide to better understand the main role of autophagy during skeletal muscle disuse and its regulation by Beta2-adrenoceptor. We expect that clarifying the modulation of autophagy components as well as their intermolecular interactions will be crucial for future therapeutic strategies against skeletal myopathy. The current research proposal (BEPE Internship Abroad) is a joint effort between the labs of Dr. Julio C.B. Ferreira and Dr. Roberta A. Gottlieb. Dr. Roberta A. Gottlieb's (Cedars-Sinai Medical Center, Los Angeles, USA) lab focuses on translational research with emphasis on adaptive autophagy in cardiac and skeletal muscles. Her lab has several tools to better characterize and understand autophagy in mammals. Therefore, this international cooperation will allow us to investigate the involvement of autophagy in the positive effects of Beta2-adrenoceptor signaling pathway during skeletal muscle pathophysiology. We believe this partnership will help us to unravel the mechanisms involved in skeletal muscle weakness/wasting.
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