•Outcome measures and clinical trial readiness are needed in mitochondrial diseases.•Primary mitochondrial myopathy has been defined clinically and genetically.•This consensus supplies guidance to ...clinical researchers and industry.
Key points
Chronic obstructive pulmonary disease (COPD) is largely caused by smoking, and patient limb muscle exhibits a fast fibre shift and atrophy.
We show that this fast fibre shift is associated ...with type grouping, suggesting recurring cycles of denervation–reinnervation underlie the type shift.
Compared to patients with normal fat‐free mass index (FFMI), patients with low FFMI exhibited an exacerbated fibre type shift, marked accumulation of very small persistently denervated muscle fibres, and a blunted denervation‐responsive transcript profile, suggesting failed denervation precipitates muscle atrophy in patients with low FFMI.
Sixteen weeks of passive tobacco smoke exposure in mice caused neuromuscular junction degeneration, consistent with a key role for smoke exposure in initiating denervation in COPD.
A neurological basis for the fast fibre shift and atrophy seen in limb muscle of patients with chronic obstructive pulmonary disease (COPD) has not been considered previously. The objective of our study was: (1) to determine if denervation contributes to fast fibre shift and muscle atrophy in COPD; and (2) to assess using a preclinical smoking mouse model whether chronic tobacco smoke (TS) exposure could initiate denervation by causing neuromuscular junction (NMJ) degeneration. Vastus lateralis muscle biopsies were obtained from severe COPD patients n = 10 with low fat‐free mass index (FFMI), 65 years; n = 15 normal FFMI, 65 years) and healthy age‐ and activity‐matched non‐smoker control subjects (CON; n = 11, 67 years), to evaluate morphological and transcriptional markers of denervation. To evaluate the potential for chronic TS exposure to initiate these changes, we examined NMJ morphology in male adult mice following 16 weeks of passive TS exposure. We observed a high proportion of grouped fast fibres and a denervation transcript profile in COPD patients, suggesting that motor unit remodelling drives the fast fibre type shift in COPD patient limb muscle. A further exacerbation of fast fibre grouping in patients with low FFMI, coupled with blunted reinnervation signals, accumulation of very small non‐specific esterase hyperactive fibres and neural cell adhesion molecule‐positive type I and type II fibres, suggests denervation‐induced exhaustion of reinnervation contributes to muscle atrophy in COPD. Evidence from a smoking mouse model showed significant NMJ degeneration, suggesting that recurring denervation in COPD is probably caused by decades of chronic TS exposure.
Key points
Chronic obstructive pulmonary disease (COPD) is largely caused by smoking, and patient limb muscle exhibits a fast fibre shift and atrophy.
We show that this fast fibre shift is associated with type grouping, suggesting recurring cycles of denervation–reinnervation underlie the type shift.
Compared to patients with normal fat‐free mass index (FFMI), patients with low FFMI exhibited an exacerbated fibre type shift, marked accumulation of very small persistently denervated muscle fibres, and a blunted denervation‐responsive transcript profile, suggesting failed denervation precipitates muscle atrophy in patients with low FFMI.
Sixteen weeks of passive tobacco smoke exposure in mice caused neuromuscular junction degeneration, consistent with a key role for smoke exposure in initiating denervation in COPD.
Dramatic tissue variation in mitochondrial heteroplasmy has been found to exist in patients with sporadic mitochondrial DNA (mtDNA) mutations. Despite high abundance in mature skeletal muscle, levels ...of the causative mutation are low or undetectable in satellite cells. The activation of these typically quiescent mitotic cells and subsequent shifting of wild-type mtDNA templates to mature muscle have been proposed as a means of restoring a more normal mitochondrial genotype and function in these patients. Because resistance exercise is known to serve as a stimulus for satellite cell induction within active skeletal muscle, this study sought to assess the therapeutic potential of resistance training in eight patients with single, large-scale mtDNA deletions by assessing: physiological determinants of peak muscle strength and oxidative capacity and muscle biopsy-derived measures of damage, mtDNA mutation load, level of oxidative impairment and satellite cell numbers. Our results show that 12 weeks of progressive overload leg resistance training led to: (i) increased muscle strength; (ii) myofibre damage and regeneration; (iii) increased proportion of neural cell adhesion molecule (NCAM)-positive satellite cells; (iv) improved muscle oxidative capacity. Taken together, we believe these findings support the hypothesis of resistance exercise-induced mitochondrial gene-shifting in muscle containing satellite cells which have low or absent levels of deleted mtDNA. Further investigation is warranted to refine parameters of the exercise training protocol in order to maximize the training effect on mitochondrial genotype and treatment potential for patients with selected, sporadic mutations of mtDNA in skeletal muscle.
Peripheral muscle alterations have been recognized to contribute to disability in chronic obstructive pulmonary disease (COPD).
To describe the mitochondrial phenotype in a moderate to severe COPD ...population and age-matched controls.
Three primary aspects of mitochondrial function were assessed in permeabilized locomotor muscle fibers.
Respiration rates per milligram of fiber weight were significantly lower in COPD muscle compared with healthy age-matched control muscle under various respiratory states. However, when variations in mitochondrial volume were taken into account by normalizing respiration per unit of citrate synthase activity, differences between the two groups were abolished, suggesting the absence of specific mitochondrial respiratory impairment in COPD. H(2)O(2) production per mitochondrion was higher both under basal and ADP-stimulated states, suggesting that mitochondria from COPD muscle have properties that potentiate H(2)O(2) release. Direct assessment of mitochondrial sensitivity to Ca(2+)-induced opening of the permeability transition pore (PTP) indicated that mitochondria from patients with COPD were more resistant to PTP opening than their counterparts in control subjects.
Comparison of these results with those of studies comparing healthy glycolytic with oxidative muscle suggests that these differences may be attributable to greater type II fiber expression in COPD muscle, as mitochondria within this fiber type have respiratory function similar to that of mitochondria from type I fibers, and yet are intrinsically prone to greater release of H(2)O(2) and more resistant to PTP opening. These results thus argue against the presence of pathological mitochondrial alterations in this category of patients with COPD.
At present there are limited therapeutic interventions for patients with mitochondrial myopathies. Exercise training has been suggested as an approach to improve physical capacity and quality of life ...but it is uncertain whether it offers a safe and effective treatment for patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. The objectives of this study were to assess the effects of exercise training and detraining in eight patients with single, large-scale mtDNA deletions to determine: (i) the efficacy and safety of endurance training (14 weeks) in this patient population; (ii) to determine the effect of more prolonged (total of 28 weeks) exercise training upon muscle and cardiovascular function and (iii) to evaluate the effect of discontinued training (14 weeks) upon muscle and cardiovascular function. Our results show that: (i) 14 weeks of exercise training significantly improved tolerance of submaximal exercise and peak capacity for work, oxygen utilization and skeletal muscle oxygen extraction with no change in the level of deleted mtDNA; (ii) continued training for an additional 14 weeks maintained these beneficial adaptations; (iii) the cessation of training (detraining) resulted in loss of physiological adaptation to baseline capacity with no overall change in mutation load. Patients' self assessment of quality of life as measured by the SF-36 questionnaire improved with training and declined with detraining. Whilst our findings of beneficial effects of training on physiological outcome and quality of life without increases in the percentage of deleted mtDNA are encouraging, we did not observe changes in mtDNA copy number. Therefore there remains a need for longer term studies to confirm that endurance exercise is a safe and effective treatment for patients with mitochondrial myopathies. The effects of detraining clearly implicate physical inactivity as an important mechanism in reducing exercise capacity and quality of life in patients with mitochondrial myopathy.
Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no ...comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes.
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 (VO2, 16 ± 8 ml/kg/min) were significantly lower (P < 0.01) than in controls (mean work capacity = 2.2 ± 0.7 W/kg; VO2 = 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 O2 difference (a–vO2); 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 VO2 and peak systemic a–vO2 difference (r2 = 0.69). In the patients, the increase in cardiac output relative to VO2 (mean ΔQ/ΔVO2 = 15.0 ± 13.6; range 3.3–73) and ventilation (mean peak VE/VO2 = 65 ± 24; range 21–104) were exaggerated compared with controls (mean ΔQ/ΔVO2 = 5.1 ± 0.7; VE/VO2 = 41.2 ± 7.4, P < 0.01). There was a negative exponential relationship between ΔQ/ΔVO2 and peak systemic a–vO2 difference (r2 = 0.92) and between peak VE/VO2 and systemic a–vO2 difference (r2 = 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 (r2 = 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.
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