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The phosphodiesterase-4 inhibitor roflumilast reverts proteolysis in skeletal muscle cells of patients with COPD cachexia
- Source :
- Recercat. Dipósit de la Recerca de Catalunya, instname
- Publisher :
- American Physiological Society
-
Abstract
- Peripheral muscle weakness and mass loss are characteristic features in severe chronic obstructive pulmonary disease (COPD). We hypothesized that the phosphodiesterase (PDE)-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 μM roflumilast N-oxide (RNO) for three time cohorts (1, 6, and 24 h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting. In COPD patients at 6 h RNO treatment, myotube tyrosine release, total protein ubiquitination, and tripartite motif-containing protein 32 levels were significantly lower than healthy controls, whereas at 24 h RNO treatment, myotube myosin heavy chain ( MyHC) -I and MyHC-IIx expression levels were upregulated in both patients and controls. In the 6-h RNO cohort, in patients and controls, myotube expression of nuclear factor (erythroid-derived 2)-like 2 ( NRF2) and its downstream antioxidants sirtuin-1, FGF-inducible 14, and insulin-like growth factor-1 was upregulated, whereas that of myocyte-specific enhancer factor 2C, myogenic differentiation, myogenin, myostatin, atrogin-1, and muscle RING-finger protein-1 was downregulated. In myotubes of severe COPD patients with cachexia, roflumilast-induced cAMP signaling exerts beneficial effects by targeting muscle protein breakdown (tyrosine release), along with reduced expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In both patients and controls, roflumilast also favored antioxidant defense through upregulation of the NRF2 pathway and that of the histone deacetylase sirtuin-1, whereas it improved the expression of slow- and fast-twitch myosin isoforms. These findings show that muscle dysfunction and wasting may be targeted by roflumilast-induced cAMP signaling in COPD. These results have potential therapeutic implications, as this PDE-4 inhibitor is currently available for the treatment of systemic inflammation and exacerbations in patients with severe COPD. NEW & NOTEWORTHY In myotubes of cachectic chronic obstructive pulmonary disease (COPD) patients, cAMP signaling exerted beneficial effects by targeting muscle proteolysis and reducing gene expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In myotubes of patients and controls, roflumilast also favored antioxidant defense through upregulation of the nuclear factor (erythroid-derived 2)-like 2 pathway, of sirtuin-1, and of gene expression of slow- and fast-twitch isoforms. These findings have potential clinical implications for the treatment of muscle wasting in patients with COPD and cachexia. Support for this study was provided by CIBERES, FIS 14/00713 (FEDER), SAF-2014-54371-R, SEPAR 2016, FUCAP 2016 (Spain), and an unrestricted grant from Takeda (Japan). E. Barreiro was a recipient of the ERS COPD Research Award 2008.
- Subjects :
- 0301 basic medicine
Cyclopropanes
Male
medicine.medical_specialty
Physiology
Proteolysis
Muscle Fibers, Skeletal
Aminopyridines
Muscle Proteins
COPD-induced muscle wasting
Cachexia
03 medical and health sciences
Pulmonary Disease, Chronic Obstructive
Physiology (medical)
Internal medicine
Myosin
Gene expression
Antioxidant defense
medicine
Autophagy
Humans
Muscle, Skeletal
Roflumilast
COPD
Muscle Weakness
Myosin heavy chain myotubes
medicine.diagnostic_test
Myogenesis
business.industry
Skeletal muscle
Middle Aged
medicine.disease
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Cross-Sectional Studies
Case-Control Studies
Benzamides
Female
Phosphodiesterase 4 Inhibitors
business
Biomarkers
medicine.drug
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Recercat. Dipósit de la Recerca de Catalunya, instname
- Accession number :
- edsair.doi.dedup.....bfa5423aba70a2c0cac1a7e3acccc0b9