Regulation of muscle oxidative phenotype by hypoxia in Chronic Obstructive Pulmonary Disease and Chronic Heart Failure

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 PPARγ co-activator-1 (PGC-1)
whereas hypoxia-inducible factor-1α (HIF-1α) 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-1α.
Another possible mechanism by which hypoxia may affect muscle oxidative
capacity could be indirectly through a cross-talk with adipose tissue. Adipose
tissue has been shown to be an active producer of inflammatory mediators, like
TNF-α, IL-6, leptin and adiponectin. It is also well described that hypoxia in
adipose tissue, either as an effect of hypoxemia or defects in fat tissue
itself, results in an enhanced pro-inflammatory cytokine release. Recent
unpublished data from our lab clearly show that TNF-* leads to a loss of
oxidative phenotype in cultured muscle cells and in COPD increased TNF-α
expression in skeletal muscle cells was associated with impaired oxidative
capacity of these cells. Since both COPD and CHF are highly associated with
systemic inflammation, we hypothesize that excessive release of inflammatory
mediators by adipose tissue due to hypoxia could also affect the oxidative
capacity of skeletal muscle cells in COPD and CHF.

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

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 undergo an adipose tissue biopsy that will be histologically
investigated and tested for markers for hypoxia and inflammation. Patients will
be characterized thoroughly including measurement of lung function, exercise
capacity and muscle function.

Subjects that participate in this study will be asked to come to the hospital
twice. During these visits, they will undergo lung function testing,
measurement of height, weight, whole-body fat free mass and muscle function.
Blood flow in the arm is measured by venous occlusion plethysmography. Subjects
will have to fill in a questionnaire and wear an accelerometer for one week.
One adipose tissue biopsy will be taken at rest, and one or two muscle biopsies
will be taken in combination with an exercise test (cycle ergometry). Before
and during the exercise test, an electrocardiogram will be made and muscle
oxygenation will be measured by an infra-red probe. A venous blood sample will
be taken from all subjects for determination of oxygen markers and markers for
inflammation. Minor risks are associated with the muscle biopsy. These risks
include subsequent bleeding, muscle aching, infection and minor nerve damage.
The minor risks associated with an adipose tissue biopsy are subsequent
bleeding, minor nerve damage and infection. Drawing of arterial blood from the
radial artery can be associated with bleeding and minor nerve damage. Subjects
do not benefit personally from participating in this study, but contribute to
research that might be beneficial for large patient groups in the future.