Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms

Abstract

Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low Vo(2peak) (28 ± 9% of predicted) and exaggerated systemic O(2) delivery relative to O(2) utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high VE/VO(2peak), (MM = 104 ± 18; C = 42 ± 8, P ≤ 0.001), and Ve/VCO(2peak)(,) (MM = 54 ± 9; C = 34 ± 7, P ≤ 0.01); a steeper slope of increase in ΔVE/ΔVCO(2) (MM = 50.0 ± 6.9; C = 32.2 ± 6.6, P ≤ 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 ± 0.31, C = 1.25 ± 0.03, P ≤ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower Pa(CO(2)) and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated VE/VO(2), VE/VCO(2), and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation.

Fig. 1.

Ventilatory and perceptional response during incremental exercise as function of workload in mitochondrial myopathy patients (MM; A, C, E, G, I) and control subjects (C; B, D, F, H, J). V̇e, expired minute ventilation; V̇e/V̇o₂, ventilatory equivalent for O₂; V̇e/V̇co₂, ventilatory equivalent for CO₂; RER, respiratory exchange ratio, V̇co₂/V̇o₂; RPB, rating for perceived breathing effort. Starting values are resting values for both groups in some MM patients followed by unloaded cycling.

Fig. 2.

Arterial blood lactate (A, B), pH (C, D), blood gases (Pa_O2; E, F, and Pa_CO2; G, H), and standard bicarbonate (Std HCO₃⁻; I and J) response during incremental exercise as a function of workload. Starting values are resting values for both groups, in some MM patients followed by unloaded cycling.

Fig. 3.

Exercise ventilatory response. VCP, slope ΔV̇e/ΔV̇co₂ from rest to the ventilatory compensation point; Peak, V̇e/V̇co₂ slope from rest to peak exercise. ††Significantly different from the control group, P ≤ 0.01.

Fig. 4.

Maximal and tidal flow-volume loops typical for two age ranges measured at rest and during exercise. Younger MM patient, 37 yr; older MM patient, 60 yr.

Fig. 5.

Ventilatory and perceptional response during recovery as function of recovery time in MM patients and C subjects. V̇e, expired minute ventilation (A, B); V̇e/V̇o₂, ventilatory equivalent for O₂ (C and D); V̇e/V̇co₂, ventilatory equivalent for CO₂ (E and F); RER, respiratory exchange ratio, V̇co₂/V̇o₂ (G and H); and RPB (I and J). Starting values are peak exercise values for both groups.

Fig. 6.

Arterial blood lactate, pH, blood gases (Pa_O2, Pa_CO2), and standard bicarbonate (Std HCO₃⁻) response during recovery as a function of recovery time. Starting values are peak exercise values for both groups.