Dysregulated myogenesis and autophagy in genetically induced pulmonary emphysema
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA747279 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15177581_1.fastq.gz | Fastqsanger.gz | |||
| SRR15177581_2.fastq.gz | Fastqsanger.gz | |||
| SRR15177582_1.fastq.gz | Fastqsanger.gz | |||
| SRR15177582_2.fastq.gz | Fastqsanger.gz | |||
| SRR15177583_1.fastq.gz | Fastqsanger.gz |
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Project description:Patients with chronic obstructive pulmonary disease (COPD)-pulmonary emphysema often develop locomotor muscle dysfunction, which is independently associated with disability and higher mortality in that population. Muscle dysfunction entails reduced muscle mass and force-generation capacity, which are influenced by fibers integrity. Myogenesis, which is muscle turnover driven by progenitor cells such as satellite cells, contributes to the maintenance of muscle integrity in the context of organ development and injury-repair cycles. Injurious events crucially occur in COPD patients’ skeletal muscles in the setting of exacerbations and infections which lead to acute decompensations for limited periods of time after which, patients typically fail to recover the baseline status they had before the acute event. Autophagy, which is dysregulated in muscles from COPD patients, is a key regulator of satellite cells activation and myogenesis, yet very little research has so far investigated the mechanistic role of autophagy dysregulation in COPD muscles. Using a genetically inducible murine model of COPD-driven muscle dysfunction and confirmed with a second genetic animal model, we found a significant myogenic dysfunction associated with a reduced proliferative capacity of freshly isolated satellite cells. Transplantation experiments followed by lineage tracing suggest that an intrinsic defect in satellite cells, and not in the COPD environment, plays a dominant role in the observed myogenic dysfunction. RNA sequencing analysis of freshly isolated satellite cells suggests cell cycle and autophagy dysregulation, which is confirmed by a direct observation of COPD mice satellite cells fluorescent-tracked autophagosome formation. Moreover, spermidine-induced autophagy stimulation leads to improved satellite cells autophagosome turnover, replication rate and myogenesis. Our data suggests that pulmonary emphysema causes a disrupted myogenesis, which could be improved with stimulation of autophagy and satellite cells activation, leading to an attenuated muscle dysfunction in this context.
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Project description:Skeletal muscle wasting and reduced oxidative capacity coexist in patients with COPD/pulmonary emphysema and are independently associated with higher mortality. Whether reduced respiration contributes to muscle atrophy in that setting remains unknown. We have previously shown that a mouse with genetically induced COPD/pulmonary emphysema recapitulates muscle dysfunction features present in patients’ muscles, including reduced expression and activity of succinate dehydrogenase (SDH), which are partially reversed by genetic gain of SDH function. Previous research suggests that succinate accumulation, a by-product of SDH inhibition, can increase respiratory capacity of skeletal muscle. Here, we generated an inducible, muscle-specific SDH-C knockout mouse which demonstrates lower mitochondrial oxygen consumption and oxidative fibers’ contractility, associated with overall reduced exercise endurance. These changes are partially offset by mitochondrial complex I-dependent respiration, a respiratory pattern replicated in the muscles from the COPD/pulmonary emphysema genetic model. Moreover, while mice skeletal muscle SDH-C knockout causes an early succinate accumulation associated with a downregulated transcriptome, these changes do not correlate with the proteomic landscape; and animals muscle mass, fiber-type composition, and dry body mass constituents remain unaltered. We preset the first conditional, skeletal muscle-specific SDH-C knockout animal and demonstrate that while SDH-C regulates fibers respiration in genetically induced pulmonary emphysema, it does not control muscle mass.
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Project description:Skeletal muscle wasting and reduced oxidative capacity coexist in patients with COPD/pulmonary emphysema and are independently associated with higher mortality. Whether reduced respiration contributes to muscle atrophy in that setting remains unknown. We have previously shown that a mouse with genetically induced COPD/pulmonary emphysema recapitulates muscle dysfunction features present in patients’ muscles, including reduced expression and activity of succinate dehydrogenase (SDH), which are partially reversed by genetic gain of SDH function. Previous research suggests that succinate accumulation, a by-product of SDH inhibition, can increase respiratory capacity of skeletal muscle. Here, we generated an inducible, muscle-specific SDH-C knockout mouse which demonstrates lower mitochondrial oxygen consumption and oxidative fibers’ contractility, associated with overall reduced exercise endurance. These changes are partially offset by mitochondrial complex I-dependent respiration, a respiratory pattern replicated in the muscles from the COPD/pulmonary emphysema genetic model. Moreover, while mice skeletal muscle SDH-C knockout causes an early succinate accumulation associated with a downregulated transcriptome, these changes do not correlate with the proteomic landscape; and animals muscle mass, fiber-type composition, and dry body mass constituents remain unaltered. We preset the first conditional, skeletal muscle-specific SDH-C knockout animal and demonstrate that while SDH-C regulates fibers respiration in genetically induced pulmonary emphysema, it does not control muscle mass.
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Project description:Gene expression profiling of lung tissue from undiseased (NML), 'usual' emphysema (EML), and Alpha-1 Antitrypsin Deficiency-related emphysema (ADL). Keywords = Emphysema Keywords = COPD Keywords = Alpha-1 Antitrypsin Deficiency Keywords: ordered
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Project description:Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.
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Project description:Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.
2024-05-31 | GSE266865 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.
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