Muscle hypertrophy in hypoxia with inflammation is controlled by bromodomain and extra-terminal domain proteins.
Clovis ChabertSaadi KhochbinSophie RousseauxRebecca FurzeNicholas SmithersRabinder K PrinjhaUwe SchlattnerChristophe PisonHervé DubouchaudPublished in: Scientific reports (2017)
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.
Keyphrases
- dna methylation
- chronic obstructive pulmonary disease
- oxidative stress
- skeletal muscle
- pulmonary hypertension
- minimally invasive
- ejection fraction
- newly diagnosed
- endothelial cells
- poor prognosis
- clinical trial
- physical activity
- inflammatory response
- cystic fibrosis
- prognostic factors
- histone deacetylase
- atrial fibrillation
- immune response
- coronary artery disease
- high intensity
- study protocol
- drug delivery
- placebo controlled
- double blind