Quadriceps muscle weakness and atrophy are associated with a differential epigenetic profile in advanced COPD

Abstract

Epigenetic mechanisms regulate muscle mass and function in models of muscle dysfunction and atrophy. We assessed whether quadriceps muscle weakness and atrophy are associated with a differential expression profile of epigenetic events in patients with advanced COPD (chronic obstructive pulmonary disease). In vastus lateralis (VL) of sedentary severe COPD patients (n=41), who were further subdivided into those with (n=25) and without (n=16) muscle weakness and healthy controls (n=19), expression of muscle-enriched miRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), growth and atrophy signalling markers, total protein and histone acetylation, transcription factors, small ubiquitin-related modifier (SUMO) ligases and muscle structure were explored. All subjects were clinically evaluated. Compared with controls, in VL of all COPD together and in muscle-weakness patients, expression of miR-1, miR-206 and miR-27a, levels of lysine-acetylated proteins and histones and acetylated histone 3 were increased, whereas expression of HDAC3, HDAC4, sirtuin-1 (SIRT-1), IGF-1 (insulin-like growth factor-1) were decreased, Akt (v-akt murine thymoma viral oncogene homologue 1) expression did not differ, follistatin expression was greater, whereas myostatin expression was lower, serum reponse factor (SRF) expression was increased and fibre size of fast-twitch fibres was significantly reduced. In VL of severe COPD patients with muscle weakness and atrophy, epigenetic events regulate muscle differentiation rather than proliferation and muscle growth and atrophy signalling, probably as feedback mechanisms to prevent those muscles from undergoing further atrophy. Lysine-hyperacetylation of histones may drive enhanced protein catabolism in those muscles. These findings may help design novel therapeutic strategies (enhancers of miRNAs promoting myogenesis and acetylation inhibitors) to selectively target muscle weakness and atrophy in severe COPD.

Normativa SEPAR sobre disfunción muscular de los pacientes con enfermedad pulmonar obstructiva crónica

“…1B). Finalmente, también se ha demostrado que mecanismos como la proteólisis, la apoptosis, la autofagia y la epigenética están involucrados en la fisiopatología de la disfunción muscular periférica de dichos enfermos 9,[15][16][17][18][19] .…”

“…2B). Sin embargo, en la EPOC avanzada, idénti-cos mecanismos biológicos 8,9,[15][16][17][18][19]26 a los descritos en la disfunción muscular periférica afectarían al diafragma predominando sobre los mecanismos adaptativos ( fig. 2B).…”

Premature aging in chronic kidney disease and chronic obstructive pulmonary disease

“…A cross-sectional study has shown that global DNA hypermethylation is associated with inflammation and increased mortality in CKD [24]. Recent evidence has shown that mi-RNAs may not only play an important role in the epigenetic regulation of vascular abnormalities in chronic organ disease [25], but also in the pathogenesis of muscle wasting [26]. A downregulation of miR-1 was associated with an increase in histone deacetylase 4 in the vastus lateralis muscle of COPD patients.…”

Skeletal Muscle Dysfunction: From Chronic Respiratory Disease to Critically Ill Patients

“…A fibre-type switch towards a less fatigue-resistant phenotype (from slow-twitch to fast-twitch fibres) is a major feature in the vastus lateralis of patients with advanced COPD [33][34][35][36] . Furthermore, fast-twitch fibres are also of smaller size in patients with advanced COPD and poor muscle mass [33][34][35] , thus contributing to muscle weakness. Additionally, factors such as aging 37 , malnutrition 38 , and systemic corticosteroid treatment 39 may worsen the fasttwitch fibre atrophy observed in COPD.…”

“…1). Other relevant molecular and cellular events that have been shown to mediate muscle mass loss and dysfunction in COPD from different aetiological factors are increased proteolysis 33,35 , apoptosis 62 , epigenetic mechanisms 34,[65][66][67][68] , and increased autophagy 35 ( Fig. 3).…”