The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients

Abstract

Impaired skeletal muscle oxidative phosphorylation in patients with severe mitochondrial respiratory chain defects results in disabling exercise intolerance that is associated with a markedly blunted capacity of muscle to increase oxygen utilization in relation to circulatory and ventilatory responses that increase oxygen delivery to muscle during exercise. The range of oxidative limitation and the relationship between the severity of oxidative defects and physiological responses to exercise among a broader spectrum of mitochondrial respiratory chain defects has not been defined. We evaluated oxidative capacity and circulatory and ventilatory responses to maximal cycle exercise in 40 patients with biochemically and/or molecularly defined mitochondrial myopathy (MM) associated with varying levels of exercise tolerance, and compared responses with those in healthy sedentary individuals. In the MM patients, mean peak work capacity (0.88 +/- 0.6 W/kg) and oxygen uptake (VO(2), 16 +/- 8 ml/kg/min) were significantly lower (P < 0.01) than in controls (mean work capacity = 2.2 +/- 0.7 W/kg; VO(2) = 32 +/- 7 ml/kg/min), but the patient range was broad (0.17-3.2 W/kg; 6-47 ml/kg/min). Oxidative capacity in patients was limited by the ability of muscle to extract available oxygen from blood [mean peak systemic arteriovenous O(2) difference (a-vO(2)); patients = 7.7 +/- 3.5, range 2.7-17.6 ml/dl, controls = 15.2 +/- 2.1 ml/dl], as indicated by a linear correlation between peak VO(2) and peak systemic a-vO(2) difference (r(2) = 0.69). In the patients, the increase in cardiac output relative to VO(2) (mean DeltaQ/DeltaVO(2) = 15.0 +/- 13.6; range 3.3-73) and ventilation (mean peak VE/VO(2) = 65 +/- 24; range 21-104) were exaggerated compared with controls (mean DeltaQ/DeltaVO(2) = 5.1 +/- 0.7; VE/VO(2) = 41.2 +/- 7.4, P < 0.01). There was a negative exponential relationship between DeltaQ/DeltaVO(2) and peak systemic a-vO(2) difference (r(2) = 0.92) and between peak VE/VO(2) and systemic a-vO(2) difference (r(2) = 0.53). In patients with heteroplasmic mtDNA mutations, we found an inverse relationship between the proportion of skeletal muscle mutant mtDNA and peak extraction of available oxygen during exercise (r(2) = 0.70). We conclude that the degree of exercise intolerance in MM correlates directly with the severity of impaired muscle oxidative phosphorylation as indicated by the peak capacity for muscle oxygen extraction. Exaggerated circulatory and ventilatory responses to exercise are direct consequences of the level of impaired muscle oxidative phosphorylation and increase exponentially in relation to an increasing severity of oxidative impairment. In patients with mtDNA mutations, muscle mutation load governs mitochondrial capacity for oxidative phosphorylation and determines exercise capacity.

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).…”

“…In this context, a reduced, but linear, Δ O 2 /ΔWR is thought to represent decreased O 2 utilization (1,2). Assuming that patients' ability to increase cardiac output was not impaired (see Study limitations), a lower C(a-v)O 2 (i.e., reduced O 2 extraction) is the most likely explanation for a reduced Δ O 2 /ΔWR as demonstrated by Taivassalo et al (19) and, more recently, by Grassi et al (32) using near-infrared spectroscopy. Considering that Δ O 2 /ΔWR was significantly related to several indicators of aerobic metabolism, this relationship seems to be useful to indicate patients in whom O 2 extraction is particularly impaired.…”

“…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.…”

Recommendations on the use of exercise testing in clinical practice

“…However, milder forms of myopathy as well as significant muscle deconditioning (see later) may be difficult to differentiate from mild cardiovascular disease. Patients with metabolic myopathies may also present with muscle pain during or after exhausting exercise [41,43,59] or with cramps during exercise (myoadenylate deaminase deficiency) [60].…”

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

“…A series of such collaborative trials have been conducted at the University of Texas, Southwest Medical Center [49][50][51]. These initial trials were open label and sequential, recruiting patients with mtDNA mutations, and, starting with baseline evaluation, bicycle exercise for 14 weeks and final re-evaluation.…”