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 V O2peak (28 Ϯ 9% of predicted) and exaggerated systemic O 2 delivery relative to O2 utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high V E/V O2peak, (MM ϭ 104 Ϯ 18; C ϭ 42 Ϯ 8, P Յ 0.001), and V E/V CO2peak, (MM ϭ 54 Ϯ 9; C ϭ 34 Ϯ 7, P Յ 0.01); a steeper slope of increase in ⌬V E/⌬V CO2 (MM ϭ 50.0 Ϯ 6.9; C ϭ 32.2 Ϯ 6.6, P Յ 0.01); and elevated peak respiratory exchange ratio (RER), (MM ϭ 1.95 Ϯ 0.31, C ϭ 1.25 Ϯ 0.03, P Յ 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 V E/V O2, V E/V CO2, 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.hyperventilation; lactic acidosis; metaboreflex; exercise; oxidative phosphorylation EXERTIONAL DYSPNEA WAS FIRST described as a symptom that limited exercise in mitochondrial myopathy (MM) in patients with a familial disorder studied by Linderholm and coworkers in the 1960s (36, 38), a disease now recognized to be attributable to a mutation in the iron-sulfur cluster scaffold (ISCU) gene (40, 42) and associated with deficiency of multiple iron-sulfur proteins, including succinate dehydrogenase and aconitase (20,21). Exertional dyspnea has since been described as a dominant feature of exercise intolerance in other mitochondrial myopathies that severely restrict muscle oxidative phosphorylation (3a, 22). Moreover, mitochondrial disease has been suggested to be an underrecognized cause of unexplained exertional dyspnea (16,25), although, these reports lacked genetic confirmation and, in most cases, did not include biochemical assessment to indicate the presence and severity of the putative mitochondrial defect (16). To better define the physiological manifestations of exertional dyspnea in mitochondrial myopathy, we have evalu...

Ventilatory response to exercise in adolescents with cystic fibrosis and mild-to-moderate airway obstruction

“…This results in a greater dependency on glycolytic energy systems at lower exercise intensities resulting in an increased VCO 2 . Higher aerobic or anaerobic glycolytic energy expenditure during exercise increases ventilation as supported by a study in patients with familial mitochondrial myopathy (Heinicke et al 2011 ). The current study showed an exaggerated VE relative to metabolic rate, indicated by high VE/VO 2 -slope values and VE/WR ratios, as well as an elevated RER, with no apparent signs of pulmonary insufficiency.…”

Genetic and hypoxic alterations of the micro RNA ‐210‐ ISCU 1/2 axis promote iron–sulfur deficiency and pulmonary hypertension

“…Such persons are plagued by a mitochondrial myopathy and lactic acidosis. Importantly, such persons also suffer from extreme exertional dyspnea which has never been fully explained by myopathy alone (Linderholm et al , ; Heinicke et al , ) but is consistent with exercise‐induced pulmonary vascular dysfunction (so‐called exercise‐induced PAH') (Tolle et al , ). Guided by our cellular and rodent findings above, we sought to determine whether persons genetically deficient in ISCU exhibit manifestations of PH either at rest or with exercise.…”

“…Advanced cardiopulmonary exercise testing revealed exertional dyspnea with a markedly depressed VO 2max (495 ml/min, 25% of predicted) that was driven largely by impaired systemic oxygen extraction [Ca-vO 2max = 4.4 m/dl (33% of predicted)], corresponding with her known mitochondrial myopathy. There was no pulmonary mechanical limit (VE max /MVV = 28%), but there was mixed lactic acidemia (2.7-7.2 mM, rest to peak exercise) and respiratory alkalemia at peak exercise (PaCO 2 = 28 mmHg, arterial pH 7.38)-the latter well described in patients with mitochondrial myopathies (Heinicke et al, 2011). Importantly, abnormally increased pulmonary vascular resistance (PVR) during exercise (maximal PVR at exercise = 135 dynes s/cm 5 , normal < 80 dynes s/cm 5 in persons < 50 years (Groves et al, 1987;Tolle et al, 2008b)] was observed, accompanied by elevated mean PAP [maximal mPAP = 31 mmHg; normal < 29 mmHg in persons < 50 years (Badesch et al, 2009)], together consistent with exercise-induced pulmonary vascular dysfunction as defined by contemporary diagnostic criteria (Tolle et al, 2008b).…”

Altered skeletal muscle (mitochondrial) properties in patients with mitochondrial DNA single deletion myopathy

“…Particularly, the lower O 2 extraction capacity of the skeletal muscle is likely to lead to a higher systemic O 2 delivery relative to O 2 utilization, i.e. a hyperkinetic circulation, causing typical symptoms of mitochondrial myopathy such as metabolic acidosis, exertional dyspnea, exercise intolerance, low exercise performance and consecutively reduced quality of life [ 10 – 13 , 29 ].…”