Interleukin-13 drives metabolic conditioning of muscle to endurance exercise.
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ABSTRACT:
SUBMITTER: Knudsen NH
PROVIDER: S-EPMC7549736 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
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Project description:This study was designed to (1) investigate the effects of acute exercise under intermittent hypoxia on muscle mRNA and protein levels, and (2) clarify the mechanisms by which exercise under intermittent hypoxia improves endurance capacity. Experiment-1: Male mice were subjected to either acute endurance exercise, exercise under hypoxia (14% O2 ), exercise under intermittent hypoxia (Int, three cycles of room air [10 min] and 14% O2 [15 min]). At 3 h after exercise under intermittent hypoxia, sirtuin-6 mRNA levels and nuclear prolyl hydroxylases-2 protein levels were significantly upregulated in white gastrocnemius muscle in the Int group. Experiment-2: Mice were assigned to sedentary control (Sed), normoxic exercise-trained (ET), hypoxic exercise-trained (HYP) or exercise-trained under intermittent hypoxia (INT) groups. Exercise capacity was significantly greater in the INT group than in the ET and HYP group. Activity levels of citrate synthase were significantly greater in the INT group than in the HYP group in soleus (SOL) and red gastrocnemius muscles. In SOL, nuclear N-terminal PGC1α levels were considerably increased by the INT training (95% confidence interval [CI]: 1.09-1.79). The INT significantly increased pyruvate dehydrogenase complex activity levels in left ventricle (LV). Monocarboxylate transporter-4 protein levels were significantly increased after the INT training in LV. Capillary-to-fiber ratio values were significantly increased in SOL and were substantially increased in LV (CI: 1.10-1.22) after the INT training. These results suggest that exercise training under intermittent hypoxia represents a beneficial strategy for increasing endurance performance via improving metabolic properties and capillary profiles in several hind-leg muscles and the heart.
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Project description:Endurance exercise is an effective therapeutic intervention with substantial pro-healthspan effects. Male Drosophila respond to a ramped daily program of exercise by inducing conserved physiological responses similar to those seen in mice and humans. Female flies respond to an exercise stimulus but do not experience the adaptive training response seen in males. Here, we use female flies as a model to demonstrate that differences in exercise response are mediated by differences in neuronal activity. The activity of octopaminergic neurons is specifically required to induce the conserved cellular and physiological changes seen following endurance training. Furthermore, either intermittent, scheduled activation of octopaminergic neurons or octopamine feeding is able to fully substitute for exercise, conferring a suite of pro-healthspan benefits to sedentary Drosophila. These experiments indicate that octopamine is a critical mediator of adaptation to endurance exercise in Drosophila.
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