Molecular signalling towards mitochondrial breakdown is enhanced in skeletal muscle of patients with chronic obstructive pulmonary disease (COPD)

P A Leermakers,H R Gosker,M Lainscak,C C De Theije,M C J M Kelders,A E M Kneppers,A M W J Schols

doi:10.1038/s41598-018-33471-2

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.

Highlights

Skeletal muscle weakness contributes to poor clinical outcome and is associated with increased morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD)[1,2]
Fission is regulated by master-regulator Dynamin 1 Like (DNM1L), which is known as Dynamin-related protein 1 (DRP1), and proteins like Mitochondrial fission 1 (FIS1), while fusion is mainly regulated on by Optic atrophy 1 (OPA1), and proteins from the Mitofusin (MFN) family[9]
BNIP3L protein levels were higher in the vastus lateralis of COPD patients compared with controls (Fig. 1A)

Summary

Introduction

Skeletal muscle weakness contributes to poor clinical outcome and is associated with increased morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD)[1,2]. Skeletal muscle oxidative capacity and mitochondrial quantity are mainly regulated by mitochondrial homeostasis, which is determined by the balance between mitochondrial biogenesis and mitochondrial breakdown[6]. Several studies have previously reported impaired skeletal muscle mitochondrial biogenesis regulation in COPD patients[3,7,8], but data on mitochondrial breakdown is limited and its relation to the loss of oxidative capacity unknown. During MDV formation, which requires PINK1 and Parkin, only a small portion of the mitochondrion is isolated from the mitochondrial network and targeted for lysosomal breakdown independently of autophagy[16,17]. Mitochondria are highly dynamic organelles, which are constantly changing in size and shape These changes are mediated through mitochondrial fission and fusion events. Fission is regulated by master-regulator Dynamin 1 Like (DNM1L), which is known as Dynamin-related protein 1 (DRP1), and proteins like Mitochondrial fission 1 (FIS1), while fusion is mainly regulated on by Optic atrophy 1 (OPA1), and proteins from the Mitofusin (MFN) family[9]

Methods

Results

Conclusion