Endoplasmic reticulum stress and unfolded protein response profile in quadriceps of sarcopenic patients with respiratory diseases.

Abstract

Impaired muscle strength and mass (sarcopenia) are common in patients with respiratory cachexia, namely chronic obstructive pulmonary disease (COPD) and in lung cancer (LC)-cachexia. Misfolded/unfolded proteins in endoplasmic reticulum (ER) induce the compensatory unfolded protein response (UPR). Expression of ER stress and UPR markers may be differentially upregulated in vastus lateralis (VL) of patients with respiratory sarcopenia associated with either a chronic condition (COPD) or subacute (LC)-cachexia. In VL specimens from 40 COPD patients (n = 21, sarcopenic, fat-free mass index [FFMI] 16 kg/m2 and n = 19, nonsarcopenic, FFMI 18 kg/m2 ), 13 patients with LC-cachexia (FFMI 17 kg/m2 ), and 19 healthy controls (FFMI 19 kg/m 2 ), expression markers of ER stress, UPR (protein kinase-like ER kinase [PERK], activating transcription factor [ATF] 6, and inositol-requiring enzyme [IRE] 1-α), oxidative stress, autophagy, proteolysis, and apoptosis (reverse transcription polymerase chain reaction and immunoblotting), and fiber atrophy (histology) were assessed. Atrophy and muscle wasting and weakness were seen in both groups of sarcopenic patients. Compared to healthy controls, in muscles of LC-cachexia patients, expression of ER stress markers and UPR (three arms) was significantly upregulated, while in sarcopenic COPD, expression of a few ER stress markers and IRE1-α arm was upregulated. ER stress and an exaggerated UPR were observed in the VL muscle of patients with respiratory sarcopenia. The three branches of UPR were similarly upregulated in muscles of cancer cachectic patients, whereas in sarcopenic COPD patients, only IRE1 was upregulated. The differential profile of muscle UPR in chronic and subacute respiratory conditions offers a niche for the design of specific novel therapeutic approaches.