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Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.

ABSTRACT: Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.

SUBMITTER: Balnis J

PROVIDER: S-EPMC11338223 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.

Balnis Joseph J Tufts Ankita A Jackson Emily L EL Drake Lisa A LA Singer Diane V DV Lacomis David D Lee Chun Geun CG Elias Jack A JA Doles Jason D JD Maher L James LJ Jen Annie A Coon Joshua J JJ Jourd'heuil David D Singer Harold A HA Vincent Catherine E CE Jaitovich Ariel A

Science advances 20240821 34

Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH kno ...[more]

PMID: 39167644

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Project description:Patients with chronic obstructive pulmonary disease (COPD) usually develop skeletal muscle dysfunction, which represents a major comorbidity in these patients and is strongly associated with mortality and other poor outcomes. Although clinical data indicates that accelerated protein degradation and metabolic disruption are common associations of muscle dysfunction in COPD, there is very limited data on the mechanisms regulating the process, in part, due to the lack of research performed on a validated animal model of pulmonary emphysema. This model deficiency complicates the translational value of data generated with highly reductionist settings. Here, we use an established transgenic animal model of COPD based on inducible IL-13-driven pulmonary emphysema (IL-13TG) to interrogate the mechanisms of skeletal muscle dysfunction. Skeletal muscles from these emphysematous mice develop most features present in COPD patients, including atrophy, decreased oxygen consumption, and reduced force-generation capacity. Analysis of muscle proteome indicates downregulation of succinate dehydrogenase C (SDH-C), which correlates with reduced enzymatic activity, also consistent with previous clinical observations. Ontology terms identified with human data, such as ATP binding/bioenergetics are also downregulated in this animal's skeletal muscles. Moreover, chronic exercise can partially restore muscle mass, metabolic and force-generation capacity, and SDH activity in COPD mice. We conclude that this animal model of COPD/emphysema is an adequate platform to further investigate mechanisms of muscle dysfunction in this setting and demonstrates multiple approaches that can be used to address specific mechanisms regulating this process.NEW & NOTEWORTHY Skeletal muscle dysfunction is a relevant comorbidity in patients with chronic obstructive pulmonary disease (COPD). Mechanistic research in the area has so far been accomplished with models based on specific exposures to otherwise healthy animals, and no investigation using an established and validated animal model of COPD has been accomplished. We present an animal model of COPD that was previously shown to recapitulate pulmonary functional and histologic features present in patients with COPD, and demonstrates most of the features present in patients with pulmonary emphysema-associated muscle dysfunction, which we proposed as an adequate tool to develop mechanistic research in the area.

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.

Dataset Information

Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.

Publications

Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.

Similar Datasets

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