Regulation of muscle oxidative phenotype by hypoxia in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Heart Failure (CHF)

Rationale:

Chronic Obstructive Pulmonary Disease (COPD) and Chronic Heart Failure (CHF) are major causes of morbidity and mortality throughout the world. These chronic diseases are not only characterized by their local impairment, but also by their disabling impaired exercise performance. Peripheral skeletal muscle dysfunction has been identified as an important contributor to exercise intolerance. Muscular impairment involves a slow-to-fast shift in fiber types and a reduced oxidative capacity of the skeletal muscle cells. It is likely that muscle hypoxia is a major determinant of these processes, considering the fact that chronic or exercise-induced hypoxemia and underperfusion are obvious features of COPD and CHF respectively. Positive key mediators of muscle oxidative metabolism and slow twitch fiber phenotype are peroxisome proliferator-activated receptors (PPARs) and PPARã co-activator-1 (PGC-1) whereas hypoxia-inducible factor-1á (HIF-1á) is an important mediator in hypoxia sensing and stimulator of glycolytic metabolism. We hypothesize that muscle hypoxia, either chronic or intermittent (exercise-induced), is responsible for the altered muscle oxidative phenotype in COPD and CHF through modulation of the regulatory molecules PGC-1/PPARs and HIF-1á.

Systemic inflammation is believed to play an important role in COPD. Classically, it has been hypothesized that greater concentrations of circulating inflammatory mediators “spill-over” from the pulmonary compartment. However, for this no convincing evidence has been published. Alternatively, adipose tissue has been described as a potent producer of inflammation and hypoxia has been proposed to trigger an inflammatory response of the adipose tissue. We hypothesize that COPD patients have greater adipose tissue inflammatory status compared to healthy persons and that hypoxia is a mediator of this inflammatory trigger.



Objective:
The aim of this study is to identify direct markers of muscle hypoxia in COPD and CHF patients in relation to the altered muscle oxidative phenotype and the putative mediators HIF-1á and PPARs/PGC-1. Insight in the underlying molecular mechanisms of the influence of hypoxia on muscle oxidative phenotype may lead to novel intervention strategies to reverse muscle weakness in COPD and CHF.

The second aim of this study is to investigate whether adipose tissue is an extrapulmonary source of inflammation in COPD patients.



Study design:
In this cross-sectional study, muscle biopsies will be obtained before and after exercise and tested for molecular markers of hypoxia. In addition, all subjects will be characterized thoroughly including measurement of lung function, exercise capacity, muscle function and body composition measurement. Fasting adipose tissue biopsies will be obtained in COPD patients and healthy persons.

Muscle hypoxia, either chronic or intermittent (exercise-induced), is responsible for the altered muscle oxidative phenotype in chronic obstructive pulmonary disease and chronic heart failure through modulation of the regulatory molecules PGC-1/PPARs and HIF-1alpha.

COPD is associated with a higher adipose tissue inflammatory status compared to healthy persons which is associated with systemic inflammation.

Day 1 and day 8.

In this cross-sectional study, muscle biopsies will be obtained before and after exercise and tested for molecular markers of hypoxia. All subjects will be characterized thoroughly including measurement of lung function, exercise capacity, muscle function and body composition measurement. In addition, adipose tissue biopsies will be obtained from the COPD patients and healthy persons to investigate adipose tissue inflammatory status.