Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency.

Abstract

A 27-yr-old woman with lifelong severe exercise intolerance manifested by muscle fatigue, lactic acidosis, and prominent symptoms of dyspnea and tachycardia induced by trivial exercise was found to have a skeletal muscle respiratory chain defect characterized by low levels of reducible cytochromes a + a3 and b in muscle mitochondria and marked deficiency of cytochrome c oxidase (complex IV) as assessed biochemically and immunologically. Investigation of the pathophysiology of the exercise response in the patient revealed low maximal oxygen uptake (1/3 that of normal sedentary women) in cycle exercise and impaired muscle oxygen extraction as indicated by profoundly low maximal systemic arteriovenous oxygen difference (5.8 ml/dl; controls = 15.4±1.4, mean±SD). The increases in cardiac output and ventilation during exercise, normally closely coupled to muscle metabolic rate, were markedly exaggerated (more than two-to threefold normal) relative to oxygen uptake and carbon dioxide production accounting for prominent tachycardia and dyspnea at low workloads. Symptoms in our patient are similar to those reported in other human skeletal muscle respiratory chain defects involving complexes I and III, and the exaggerated circulatory response resembles that seen during experimental inhibition of the mitochondrial respiratory chain. These results suggest that impaired oxidative phosphorylation in working muscle disrupts the normal regulation of cardiac output and ventilation relative to muscle metabolic rate in exercise.

Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise

“…Patients with MM had increased cardiorespiratory responses to the metabolic demands during progressive exercise compared to healthy controls (Table 2; P < 0.01) as previously described (16)(17)(18)(19)(20). There were significant inverse relationships between Δ O 2 /ΔWR (S 1 , S 2 and S T ) and submaximal cardiovascular (ΔHR/Δ O 2 ) and ventilatory (Δ E/Δ CO 2 ) responses in patients with MM (P < 0.05).…”

“…Mitochondrial myopathy (MM) is the collective term for disease conditions in which the diminished rate of cellular O 2 utilization may place a burden on several systems in order to enhance O 2 uptake and delivery (13)(14)(15). In fact, patients with MM commonly present hyperventilatory and hypercirculatory patterns of response to dynamic exercise (16)(17)(18)(19)(20). These abnormalities are likely to be related to the fundamental pathophysiological abnormality in MM, i.e., impaired O 2 extraction.…”

A case of respiratory muscle weakness due to cytochrome c oxidase enzyme deficiency

“…The normal extremity muscle EMG initially suggested a nonneuromuscular aetiology of respiratory failure. This has been previously reported, however [7,9].…”

“…Most cases of COX deficiency are detected in infancy [4,5], though there have been case reports in older children [6]. Presentation during adulthood has been previously reported [7][8][9][10][11], usually with either preceding lifelong respiratory symptoms or other chronic symptoms.…”

What Maintains the Metabolic Cost at Peak Aerobic Exercise in End Stage Renal Disease Patients?

“…These symptoms are thought to result from impaired mitochondrial oxidative phosphorylation, which limits the capacity of mitochondria to generate the adenosine triphosphate needed for muscle work. In many chronic diseases, physical deconditioning limits exercise tolerance [27][28][29]. It has been hypothesized that patients with mitochondrial myopathies in particular suffer from chronic inactivity [30,31] further aggravating their exercise intolerance.…”