Mechanisms of Systemic Effects - Chronic Obstructive Pulmonary Disease - page 431

characterized by decreased—not increased—cytochrome oxidase activity (47).
Likewise, exercise in patients with COPD enhances the release of amino acids
from skeletal muscle, particularly alanine and glutamine (48). This is at
variance with the normal training response and suggests the presence of
intrinsic muscle abnormalities of the intermediate amino acid metabolism (49).

B. Caloric Imbalance

When metabolic demands are not met by caloric intake, weight loss ensues
(50). Caloric intake appears to be normal (not decreased) in most patients
with COPD except, perhaps, during exacerbations of the disease (50). In
contrast, most patients with COPD show an increased basal metabolic rate,
which can, therefore, contribute to weight loss (50). Its cause(s) are also
unclear but can include—among others—(a) an increased oxygen consump-
tion of the respiratory muscles due to the increased work of breathing that
characterizes the disease (51); (b) drugs commonly used in the treatment of
COPD (e.g., b 2 agonists) (52); (c) systemic inflammation, as shown by the
relationship between metabolic derangement and increased levels of inflam-
matory mediators in COPD (20); and (d) tissue hypoxia since, in our labora-
tory, we have found a direct relationship between the activity of cytochrome
oxidase in skeletal muscle—the mitochondrial enzyme that consumes
oxygen—and the degree of arterial hypoxemia present in COPD (47).

C. Tissue Hypoxia

Several observations support a potential pathogenic role for tissue hypoxia
in the development of an SMD in COPD: (a) chronic hypoxia suppresses
protein synthesis in muscle cells, causes net loss of amino acids, and reduces
the expression of myosin heavy chain isoforms (53,54); (b) healthy subjects
at high altitude (hypobaric hypoxia) lose muscle mass (55,56); (c) skeletal
muscle from patients with COPD and chronic respiratory failure present
structural—decrease of type I fibers (57,58)—and functional alterations—
up-regulation of mitochondrial cytochrome oxidase (47)—proportional to
the severity of arterial hypoxemia; and, finally, (d) as discussed above, we
observed a direct relationship between the activity of cytochrome oxidase
in skeletal muscle and the level of arterial hypoxemia present in COPD (47).

D. Systemic Inflammation

Systemic inflammation is likely to be an important pathogenic mechanism of
an SMD in COPD. In this context, TNF a is probably of particular relevance
because it can affect muscle cells in several ways and there is evidence support-
ing that TNF a plasma levels as well as the concentration of its soluble recep-
tors (17,18,20,59,60) are increased in patients with COPD and that circulating
monocytes harvested from patients with COPD produce higher amounts of