beta(2)-adrenoceptor activation improves skeletal muscle autophagy in neurogenic myopathy

Author(s)

Campos, Juliane C. ^[1] ; Baehr, Leslie M. ^[2] ; Ferreira, Nikolas D. ^[1] ; Bozi, Luiz H. M. ^[1] ; Andres, Allen M. ^{[3, 4]} ; Ribeiro, Marcio A. C. ^[1] ; Gottlieb, Roberta A. ^{[3, 4]} ; Bodine, Sue C. ^[2] ; Ferreira, Julio C. B. ^{[5, 1]}

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Ave Prof Lineu Prestes 2415, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Iowa, Dept Internal Med, Div Endocrinol & Metab, Iowa City, IA 52242 - USA

^[3] Cedars Sinai Heart Inst, Los Angeles, CA - USA

^[4] Cedars Sinai Med Ctr, Barbra Streisand Womens Heart Ctr, Los Angeles, CA 90048 - USA

^[5] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA

• Document type: Journal article
• Source: FASEB JOURNAL; v. 34, n. 4 FEB 2020.
• Web of Science Citations: 0

Abstract

beta(2)-adrenoceptor agonists improve autophagy and re-establish proteostasis in cardiac cells; therefore, suggesting autophagy as a downstream effector of beta(2)-adrenoceptor signaling pathway. Here, we used the pharmacological and genetic tools to determine the autophagy effect of sustained beta(2)-adrenoceptor activation in rodents with neurogenic myopathy, which display impaired skeletal muscle autophagic flux. Sustained beta(2)-adrenoceptor activation using Formoterol (10 mu g kg(-1) day(-1)), starting at the onset of neurogenic myopathy, prevents disruption of autophagic flux in skeletal muscle 14 days after sciatic nerve constriction. These changes are followed by reduction of the cytotoxic protein levels and increased skeletal muscle cross-sectional area and contractility properties. Of interest, sustained administration of Formoterol at lower concentration (1 mu g kg(-1) day(-1)) induces similar improvements in skeletal muscle autophagic flux and contractility properties in neurogenic myopathy, without affecting the cross-sectional area. Sustained pharmacological inhibition of autophagy using Chloroquine (50 mg kg(-1) day(-1)) abolishes the beneficial effects of beta(2)-adrenoceptor activation on the skeletal muscle proteostasis and contractility properties in neurogenic myopathy. Further supporting an autophagy mechanism for beta(2)-adrenoceptor activation, skeletal muscle-specific deletion of ATG7 blunts the beneficial effects of beta(2)-adrenoceptor on skeletal muscle proteostasis and contractility properties in neurogenic myopathy in mice. These findings suggest autophagy as a critical downstream effector of beta(2)-adrenoceptor signaling pathway in skeletal muscle. (AU)

• FAPESP's process: 18/18627-3 - Mechanisms of exercise-induced mitophagy: a new avenue to drug discovery
• Grantee: Julio Cesar Batista Ferreira
• Support Opportunities: Scholarships abroad - Research
• FAPESP's process: 16/01633-5 - BETA2-ADRENOCEPTOR ACTIVATION COUNTERACTS SKELETAL MUSCLE WEAKNESS/WASTING: ROLE OF AUTOPHAGY
• Grantee: Juliane Cruz Campos
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 17/16540-5 - Exercise, lifespan and healthspan: a molecular and longitudinal approach to study their interactions
• Grantee: Juliane Cruz Campos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 12/14416-1 - Protein quality control profile in skeletal muscle wasting: role of beta2- adrenergic receptor
• Grantee: Juliane Cruz Campos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/50429-9 - Protein quality control in dysfunctional/atrophic skeletal muscle: roke of B2 adrenoceptor
• Grantee: Julio Cesar Batista Ferreira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/16694-2 - Impact of 4-hydroxinonenal on DICER regulation: a translational approach
• Grantee: Julio Cesar Batista Ferreira
• Support Opportunities: Regular Research Grants