PURPOSE:
The primary purpose of the proposed work is to characterize skeletal muscle function in
patients with interstitial lung disease (ILD), and to determine the physiological and
sensory consequences of impaired skeletal muscle function in ILD during exercise.
HYPOTHESES:
The hypotheses are threefold; i) patients with ILD will have impaired skeletal muscle
function when compared to healthy controls, ii) impairments in skeletal muscle function
predispose ILD patients to exercise-induced quadriceps muscle fatigue, increase the
perception of exertional dyspnea, as well as reduce exercise tolerance, and iii) delivery
of supplemental oxygen during exercise mitigates exercise-induced quadriceps muscle
fatigue, attenuates the perceived intensity of dyspnea, and improves exercise tolerance.
OBJECTIVE:
The objective of the proposed study is to comprehensively investigate skeletal muscle
dysfunction in patients with ILD and characterize its impact on dyspnea and exercise
tolerance. In doing so, the proposed work will be the first to comprehensively assess
skeletal muscle function in patients with ILD as well as determine its functional
consequences. The results will provide important insight into the putative role of
skeletal muscle dysfunction on exercise limitation in patient with ILD.
JUSTIFICATION:
ILD refers to a diverse group of diseases that share common physiological characteristics
resulting from inflammation and/or fibrosis of the lung parenchyma. ILD has an estimated
prevalence of approximately 67-81 cases per 100 000 individuals. Given the heterogeneity
of disease sub-types, it is difficult to determine a precise median survival for patients
with ILD, however; in patients with idiopathic pulmonary fibrosis, the most common ILD
sub-type, have a median survival of only 2-3 years from the time of diagnosis. For
patients with ILD, dyspnea (i.e. breathlessness) is the most common symptom. Dyspnea can
be extremely debilitating, particularly during physical exertion. The clinical
significance of dyspnea in ILD is underscored by its strong correlation with quality of
life and mortality. Patients attempt to minimize dyspnea by avoiding physical activity,
resulting in deconditioning and an associated reduction in functional capacity. The
importance of maintaining functional capacity is highlighted by the fact that ILD
patients with the lowest physical activity levels have the lowest quality of life and the
highest mortality. The effective management of dyspnea and exercise intolerance is
therefore of critical importance when considering the management of patients with ILD.
The pathophysiological mechanisms of dyspnea and exercise intolerance in ILD are complex,
multifactorial, and poorly understood. Indeed, relatively few studies that have
adequately investigated the mechanistic basis of dyspnea and exercise intolerance in
patients with ILD. It is generally agreed upon that exercise limitation in ILD is related
to the combination of altered respiratory mechanics, gas exchange impairment, and
circulatory limitation. However, it is assumed that dyspnea and exercise intolerance are
exclusively related to the respiratory and circulatory impairment associated with the
pathogenesis of ILD. While this assumption is reasonable, it ignores the potentially
crucial role of skeletal muscle dysfunction as a source of dyspnea and exercise
intolerance. Recent experimental evidence indicates that skeletal muscle dysfunction
contributes to both dyspnea and exercise intolerance in COPD.
A growing body of literature supports the notion that skeletal muscle dysfunction is
common in ILD. While the precise mechanisms remain unclear, several well-established
skeletal muscle dysfunction-promoting factors are present in many ILD patients,
including: chronic hypoxaemia, oxidative stress, pulmonary and systemic inflammation,
physical deconditioning, malnutrition, and corticosteroid use. These factors may act
individually or synergistically to impair skeletal muscle function by causing muscle
atrophy, mitochondrial dysfunction, a reduction in type I muscle fibre proportion, and
increases in intramuscular fat. To our knowledge, there is limited imaging data of
skeletal muscle morphology in ILD, and assessments of skeletal muscle oxidative capacity,
and contractile function have not been concurrently obtained. If present, skeletal muscle
dysfunction likely reduces locomotor muscle oxidative capacity, leading to premature
fatigue, increased dyspnea, and diminished exercise tolerance. Most importantly, there is
no data on the physiological effects of skeletal muscle fatigue and dysfunction on
dyspnea and exercise capacity nor whether targeted treatment options such as supplemental
oxygen (O2) delivery can attenuate muscle fatigue.
Accordingly, the aims of the proposed research are threefold: i) to characterize skeletal
muscle function in patients with ILD compared to healthy controls, ii) to determine the
influence of skeletal muscle dysfunction on dyspnea, fatigue, and exercise intolerance in
patients with ILD compared to healthy controls, and iii) to determine if improving
exercise tolerance using supplemental oxygen relieves exercise-induce skeletal muscle
fatigue in ILD patients.
RESEARCH DESIGN:
Experimental hypotheses tested using combination of research designs. To test the
hypotheses i) and ii), the investigators will use a cross sectional design. To test
hypothesis iii), the investigators will use a single-blind placebo-controlled study
design.
METHODS Participants will report to the laboratory on four separate occasions separated
by a minimum of 48 hours, and each visit will last ~2-3 hours.
Visit 1:
Participants will complete medical history screening, complete a series of questionnaires
concerning chronic activity-related dyspnea, quality of life, and physical activity.
Participants will then have their height and weight measured and perform pulmonary
function testing. Finally, participants will perform a symptom limited incremental cycle
exercise test. Detailed physiological and sensory measurements will be obtained
immediately before and throughout the incremental cycle exercise test.
Visit 1 will be intended to characterize participant's pulmonary function and exercise
capacity.
Visit 2:
Participants will undergo a magnetic resonance imaging scan to assess the volume and the
fat percentage of their quadriceps muscles They will then perform a series of tests aimed
at evaluating their quadriceps muscle function, including: i) assessment of maximum
voluntary quadriceps muscles strength, and ii) the non-invasive assessment of the
oxidative capacity of their quadriceps muscle using near-infrared spectroscopy.
Data from visit 2 will be used to address hypothesis 1 by characterizing participant's
quadriceps muscle function.
Visits 3:
Participants will perform a constant-load exercise test to exhaustion while breathing
ambient air (i.e., 20.93% oxygen). The work load will be set at 75% of the highest work
rate achieved during the incremental exercise test performed during visit 1.
Data from visits 3 and 4 will be used to address hypothesis 2 by characterizing the
effect of exercise on skeletal muscle fatigue in patients with ILD and healthy controls.
Visit 4:
Participants will perform a constant-load exercise test while breathing supplemental
oxygen (i.e., 60% oxygen). The work load will be set at 75% of the highest work rate
achieved during the incremental exercise test performed during visit 1 and the test will
be terminated once participants reach the same time that they achieved during the
constant-load exercise test on Day 3.
Data from visit 4 will be used to address hypothesis 3 by determining if supplemental
oxygen can be used to alleviate exercise-induced skeletal muscle fatigue in patients with
ILD and healthy controls.
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