Exercise increases the cost of breathing (COB) due to increased lung ventilation (
E), inducing respiratory muscles deoxygenation (
SmO
2), while the increase in workload implies
SmO
2 in locomotor muscles. This phenomenon has been proposed as
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Exercise increases the cost of breathing (COB) due to increased lung ventilation (
E), inducing respiratory muscles deoxygenation (
SmO
2), while the increase in workload implies
SmO
2 in locomotor muscles. This phenomenon has been proposed as a leading cause of exercise intolerance, especially in clinical contexts. The use of high-flow nasal cannula (HFNC) during exercise routines in rehabilitation programs has gained significant interest because it is proposed as a therapeutic intervention for reducing symptoms associated with exercise intolerance, such as fatigue and dyspnea, assuming that HFNC could reduce exercise-induced
SmO
2. SmO
2 can be detected using optical wearable devices provided by near-infrared spectroscopy (NIRS) technology, which measures the changes in the amount of oxygen bound to chromophores (e.g., hemoglobin, myoglobin, cytochrome oxidase) at the target tissue level. We tested in a study with a cross-over design whether the muscular desaturation of
m.vastus lateralis and
m.intercostales during a high-intensity constant-load exercise can be reduced when it was supported with HFNC in non-physically active adults. Eighteen participants (nine women; age: 22 ± 2 years, weight: 65.1 ± 11.2 kg, height: 173.0 ± 5.8 cm, BMI: 21.6 ± 2.8 kg·m
−2) were evaluated in a cycle ergometer (15 min, 70% maximum watts achieved in ergospirometry (
O
2-peak)) breathing spontaneously (control, CTRL) or with HFNC support (HFNC; 50 L·min
−1, fiO
2: 21%, 30 °C), separated by seven days in randomized order. Two-way ANOVA tests analyzed the
SmO
2 (
m.intercostales and
m.vastus lateralis), and changes in
E and
SmO
2·
E
−1. Dyspnea, leg fatigue, and effort level (RPE) were compared between trials by the Wilcoxon matched-paired signed rank test. We found that the interaction of factors (trial × exercise-time) was significant in
SmO
2-
m.intercostales,
E, and (
SmO
2-
m.intercostales)/
E (
p < 0.05, all) but not in
SmO
2-
m.vastus lateralis.
SmO
2-
m.intercostales was more pronounced in CTRL during exercise since 5′ (
p < 0.05). Hyperventilation was higher in CTRL since 10′ (
p < 0.05). The
SmO
2·
E
−1 decreased during exercise, being lowest in CTRL since 5′. Lower dyspnea was reported in HFNC, with no differences in leg fatigue and RPE. We concluded that wearable optical biosensors documented the beneficial effect of HFNC in COB due to lower respiratory
SmO
2 induced by exercise. We suggest incorporating NIRS devices in rehabilitation programs to monitor physiological changes that can support the clinical impact of the therapeutic intervention implemented.
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