Exercise Intolerance in Cystic Fibrosis: Importance of Skeletal Muscle

Abstract

Purpose: Exercise intolerance, evaluated by O2 consumption, predicts mortality in cystic fibrosis (CF). People with CF exhibit skeletal muscle dysfunctions that may contribute to an imbalance between O2 delivery and utilization. Sildenafil, a phosphodiesterase type 5 inhibitor, increases blood flow and improves O2 consumption, although the exact mechanisms in CF have yet to be elucidated. Thus, we hypothesized that exercise intolerance in CF is limited primarily by an impaired skeletal muscle O2 utilization, and sildenafil improves exercise tolerance in CF by addressing this mismatch between O2 demand and extraction.

Methods: Fifteen individuals with mild to moderate CF and 18 healthy controls completed an incremental exercise test and measurements of gaseous exchange, chronotropic response, hemodynamics, and O2 extraction and utilization. People with CF also completed a 4-wk treatment with sildenafil with a subsequent follow-up evaluation after treatment.

Results: Skeletal muscle O2 extraction and utilization during exercise were reduced in people with CF when compared with controls. Exercise capacity in our CF population was minimally limited by hemodynamic or chronotopic responses, whereas peripheral O2 extraction was more closely associated with exercise capacity. The study also demonstrated that 4 wk of sildenafil improved skeletal muscle O2 utilization during exercise to similar values observed in healthy individuals.

Conclusions: Individuals with mild to moderate CF exhibit exercise intolerance secondary to a reduction in O2 utilization by the exercising skeletal muscle. The present study demonstrated that 4 wk of sildenafil treatment improves the capacity of the skeletal muscle to use O2 more efficiently during exercise. Findings from the present study highlight the importance of targeting skeletal muscle O2 utilization to improve exercise tolerance in CF.

Trial registration: ClinicalTrials.gov NCT02057458.

Conflict of interest statement

CONFLICT OF INTEREST: No conflicts of interest are declared by the authors. The results of the present study do not constitute an endorsement by the American College of Sports Medicine. Results of the present study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

Copyright © 2020 by the American College of Sports Medicine.

Figures

Figure 1.. Skeletal muscle O2 utilization during exercise in patients with cystic fibrosis before and after four weeks of sildenafil and in controls.

Change in total hemoglobin (ΔtHb; panel A), oxygenated hemoglobin (ΔO2Hb; panel B) and deoxygenated hemoglobin (ΔHHb; panel C) in healthy controls (grey squares; n=14), patients with CF before (black circles; n=14) and following four weeks of sildenafil (SIL, white circles; n=11). Values are mean ± SEM. *Significantly different between patients with CF and controls. #Significantly different (p<0.05) between baseline and four weeks of treatment with sildenafil in patients with CF.

Figure 2.. Reserve capacity during exercise evaluated by the increase in O2 consumption and each component of VO2.

Box and whiskers plots of the fold change of oxygen consumption (VO2), heart rate (HR), cardiac output (CO), and peripheral O2 extraction (O2ER) from rest to peak exercise independently of resting values. Data representation in healthy controls (control; grey), patients with CF (CF BL; black), and patients with CF after four weeks of sildenafil (CF SIL; white). *Significantly different (p<0.05) between patients with CF and controls. #Significantly different (p<0.05) between baseline and four weeks of treatment with sildenafil.