Muscle hypertrophy in hypoxia with inflammation is controlled by bromodomain and extra-terminal domain proteins

Clovis Chabert,Sophie Rousseaux,Rab Prinjha,Saadi Khochbin,Christophe Pison,Nicholas Smithers,Uwe Schlattner,Hervé Dubouchaud,Rebecca Furze

doi:10.1038/s41598-017-12112-0

Abstract

Some of the Chronic Obstructive Pulmonary Disease (COPD) patients engaged in exercise-based muscle rehabilitation programs are unresponsive. To unravel the respective role of chronic hypoxia and pulmonary inflammation on soleus muscle hypertrophic capacities, we challenged male Wistar rats to repeated lipopolysaccharide instillations, associated or not with a chronic hypoxia exposure. Muscle hypertrophy was initiated by bilateral ablation of soleus agonists 1 week before sacrifice. To understand the role played by the histone acetylation, we also treated our animals with an inhibitor of bromodomains and extra terminal proteins (I-BET) during the week after surgery. Pulmonary inflammation totally inhibited this hypertrophy response under both normoxic and hypoxic conditions (26% lower than control surgery, p < 0.05), consistent with the S6K1 and myogenin measurements. Changes in histone acetylation and class IIa histone deacetylases expression, following pulmonary inflammation, suggested a putative role for histone acetylation signaling in the altered hypertrophy response. The I-BET drug restored the hypertrophy response suggesting that the non-response of muscle to a hypertrophic stimulus could be modulated by epigenetic mechanisms, including histone-acetylation dependant pathways. Drugs targeting such epigenetic mechanisms may open therapeutic perspectives for COPD patients with systemic inflammation who are unresponsive to rehabilitation.

Highlights

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and persistent airflow limitation[1]
Soleus muscle hypertrophic capacity induced by functional overload generated by surgical removal of agonist muscles was studied in response to the effect of chronic hypoxia (CH) and/or pulmonary inflammation (PI) (Fig. 1)
In animals subjected to PI, the hypertrophic capacity of soleus was totally inhibited in both normoxia (−3.64%) and hypoxia (−0.72%) when compared to the control group (Fig. 2)

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and persistent airflow limitation[1]. Up to 30% of patients do not respond to such programs[15,16] while others show lower responses compared to healthy subjects[17], even after lung transplantation[18] To explain this muscle unresponsiveness, epigenetic alterations have been proposed, such as changes in the level of the histone acetylation pattern, which could impact the gene response[19]. Our aim was to unravel the respective roles of PI and CH in the soleus muscle hypertrophic capacities induced by a bilateral ablation of its agonist muscles (plantaris and gastrocnemius) This overload model allowed the investigation of several major signaling pathways and epigenetic actors involved in proteosynthesis/lysis, with a specific focus on the role of BET proteins

Objectives

Methods

Results

Discussion

Conclusion