ABSTRACT
Loss of skeletal muscle mitochondrial oxidative capacity is well-established in patients with COPD, but the role of mitochondrial breakdown herein is largely unexplored. Currently, we studied if mitochondrial breakdown signalling is increased in skeletal muscle of COPD patients and associates with the loss of mitochondrial content, and whether it is affected in patients with iron deficiency (ID) or systemic inflammation. Therefore, mitophagy, autophagy, mitochondrial dynamics and content markers were analysed in vastus lateralis biopsies of COPD patients (N = 95, FEV1% predicted: 39.0 [31.0-53.6]) and healthy controls (N = 15, FEV1% predicted: 112.8 [107.5-125.5]). Sub-analyses were performed on patients stratified by ID or C-reactive protein (CRP). Compared with controls, COPD patients had lower muscle mitochondrial content, higher BNIP3L and lower FUNDC1 protein, and higher Parkin protein and gene-expression. BNIP3L and Parkin protein levels inversely correlated with mtDNA/gDNA ratio and FEV1% predicted. ID-COPD patients had lower BNIP3L protein and higher BNIP3 gene-expression, while high CRP patients had higher BNIP3 and autophagy-related protein levels. In conclusion, our data indicates that mitochondrial breakdown signalling is increased in skeletal muscle of COPD patients, and is related to disease severity and loss of mitochondrial content. Moreover, systemic inflammation is associated with higher BNIP3 and autophagy-related protein levels.
Subject(s)
Inflammation/genetics , Membrane Proteins/genetics , Mitochondria/genetics , Proto-Oncogene Proteins/genetics , Pulmonary Disease, Chronic Obstructive/genetics , Tumor Suppressor Proteins/genetics , Aged , Anemia, Iron-Deficiency/blood , Anemia, Iron-Deficiency/genetics , Anemia, Iron-Deficiency/pathology , Autophagy/genetics , C-Reactive Protein/metabolism , DNA, Mitochondrial/genetics , Female , Gene Expression Regulation/genetics , Humans , Inflammation/blood , Inflammation/pathology , Male , Middle Aged , Mitochondria/pathology , Mitochondrial Proteins/genetics , Mitophagy/genetics , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Pulmonary Disease, Chronic Obstructive/pathology , Signal Transduction/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
Myogenic differentiation involves myoblast fusion and induction of muscle-specific gene expression, which are both stimulated by pharmacological (LiCl), genetic, or IGF-I-mediated GSK-3ß inactivation. To assess whether stimulation of myogenic differentiation is common to ligand-mediated GSK-3ß inactivation, myoblast fusion and muscle-specific gene expression were investigated in response to Wnt-3a. Moreover, crosstalk between IGF-I/GSK-3ß/NFATc3 and Wnt/GSK-3ß/ß-catenin signaling was assessed. While both Wnt-3a and LiCl promoted myoblast fusion, muscle-specific gene expression was increased by LiCl, but not by Wnt-3a or ß-catenin over-expression. Furthermore, LiCl and IGF-I, but not Wnt-3a, increased NFATc3 transcriptional activity. In contrast, ß-catenin-dependent transcriptional activity was increased by Wnt-3a and LiCl, but not IGF-I. These results for the first time reveal a segregated regulation of myoblast fusion and muscle-specific gene expression following stimulation of myogenic differentiation in response to distinct ligand-specific signaling routes of GSK-3ß inactivation.
