Normal adult aging is associated with impaired muscle contractile function; however, to what extent cross-bridge kinetics are altered in aging muscle is not clear. We used a slacken restretch ...maneuver on single muscle fiber segments biopsied from the vastus lateralis of young adults (∼23 yr), older nonathlete (NA) adults (∼80 yr), and age-matched world class masters athletes (MA; ∼80 yr) to assess the rate of force redevelopment (ktr) and cross-bridge kinetics. A post hoc analysis was performed, and only the mechanical properties of "slow type" fibers based on unloaded shortening velocity (Vo) measurements are reported. The MA and NA were ∼54 and 43% weaker, respectively, for specific force compared with young. Similarly, when force was normalized to cross-sectional area determined via the fiber shape angularity data, both old groups did not differ, and the MA and NA were ∼43 and 48% weaker, respectively, compared with young (P < 0.05). Vo for both MA and NA old groups was 62 and 46% slower, respectively, compared with young. Both MA and NA adults had approximately two times slower values for ktr compared with young. The slower Vo in both old groups relative to young, coupled with a similarly reduced ktr, suggests impaired cross-bridge kinetics are responsible for impaired single fiber contractile properties with aging. These results challenge the widely accepted resilience of slow type fibers to cellular aging.
Abstract Purpose The way in which spirometry is interpreted can lead to misdiagnosis of chronic obstructive pulmonary disease (COPD) resulting in inappropriate treatment. We compared the clinical ...relevance of 2 criteria for defining a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1 /FVC): the fixed ratio and the lower limit of normal. Methods We analyzed data from the cross-sectional phase of the population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study. We determined associations of the spirometric criteria for airflow limitation with patient-reported adverse outcomes, including respiratory symptoms, disability, health status, exacerbations, and cardiovascular disease. Sensitivity analyses were used to explore the impact of age and severity of airflow limitation on these associations. Results We analyzed data from 4,882 patients aged 40 years and older. The prevalence of airflow limitation was 17% by fixed ratio and 11% by lower limit of normal. Patients classified as having airflow limitation by fixed ratio only had generally small, nonsignificant increases in the odds of adverse outcomes. Patients having airflow limitation based on both fixed ratio and lower limit of normal had larger, significant increases in odds. But strongest associations were seen for patients who had airflow limitation by both fixed ratio and lower limit of normal and also had a low FEV1 , defined as one less than 80% of the predicted value. Conclusions Our results suggest that use of the fixed ratio alone may lead to misdiagnosis of COPD. A diagnosis established by both a low FEV1 /FVC (according to fixed ratio and/or lower limit of normal) and a low FEV1 is strongly associated with clinical outcomes. Guidelines should be reconsidered to require both spirometry abnormalities so as to reduce overdiagnosis of COPD.
The intriguing concept of exercise training as therapy for mitochondrial disease is currently unsettled: in the unique setting of mitochondrial heteroplasmy, what are the effects of chronic exercise ...on skeletal muscle containing a mixture of mutated and wild-type mitochondrial DNA (mtDNA)? Furthermore, what are the consequences of habitual physical inactivity on mitochondrial heteroplasmy? In patients with mtDNA defects, deleterious effects of limited physical activity likely magnify the mitochondrial oxidative impairment contributing to varying degrees of exercise intolerance. Normal adaptive responses to endurance training offer the potential to increase levels of functional mitochondria, improving exercise tolerance. The few clinical studies assessing such training effects in patients with mtDNA defects have unequivocally demonstrated physiologic and biochemical adaptations that improve exercise tolerance and quality of life. Uncertain, however, is the training effect on mitochondrial heteroplasmy. To determine therapeutic advisability of endurance training, it remains imperative to establish whether: reported increases in mutant mtDNA levels can be offset by increases in absolute wild-type mtDNA levels; and chronic physical inactivity leads to a selective down-regulation of wild-type mtDNA. Resistance exercise training offers an alternate, innovative therapeutic approach in patients with sporadic mtDNA mutations; exercise-induced transfer of normal mtDNA templates from muscle satellite cells to mature myofibers, thereby lowering mutation load (increasing functional mitochondrial load). Efficacy and safety of this approach needs to be replicated in a larger group of patients. Currently, appropriate recommendation (either in support or against) exercise training in mitochondrial disease is lacking, which is frustrating for physicians and disheartening for patients. Although considerable progress has been made, an immediate urgency exists to resolve the effects of chronic exercise on skeletal muscle in patients with heteroplasmic mtDNA mutations.
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.
Context:
Patients with blocked muscle glycogen breakdown (McArdle disease) have severely reduced exercise capacity compared to healthy individuals and are not assumed to produce lactate during ...exercise.
Objectives:
The objectives were: 1) to quantify systemic and muscle lactate kinetics and oxidation rates and muscle energy utilization during exercise in patients with McArdle disease; and 2) to elucidate the role of lactate formation in muscle energy production.
Design and Setting:
This was a single trial in a hospital.
Participants:
Participants were four patients with McArdle disease and seven healthy subjects.
Intervention:
Patients and healthy controls were studied at rest, which was followed by 40 minutes of cycle-ergometer exercise at 60% of the patients' maximal oxygen uptake (∼35 W).
Main Outcome Measures:
Main outcome measures were systemic and leg skeletal muscle lactate, alanine, fatty acid, and glucose kinetics.
Results:
McArdle patients had a marked decrease in plasma lactate concentration at the onset of exercise, and the concentration remained suppressed during exercise. A substantial leg net lactate uptake and subsequent oxidation occurred over the entire exercise period in patients, in contrast to a net lactate release or no exchange in the healthy controls. Despite a net lactate uptake by the active leg, a simultaneous unidirectional lactate release was observed in McArdle patients at rates that were similar to the healthy controls.
Conclusion:
Lactate is an important energy source for contracting skeletal muscle in patients with myophosphorylase deficiency. Although McArdle patients had leg net lactate consumption, a simultaneous release of lactate was observed at rates similar to that found in healthy individuals exercising at the same very low workload, suggesting that lactate formation is mandatory for muscle energy generation during exercise.
Eccentric ergometer training (EET) is increasingly being proposed as a therapeutic strategy to improve skeletal muscle strength in various cardiorespiratory diseases, due to the principle that ...lengthening muscle actions lead to high force-generating capacity at low cardiopulmonary load. One clinical population that may particularly benefit from this strategy is chronic obstructive pulmonary disease (COPD), as ventilatory constraints and locomotor muscle dysfunction often limit efficacy of conventional exercise rehabilitation in patients with severe disease. While the feasibility of EET for COPD has been established, the nature and extent of adaptation within COPD muscle is unknown. The aim of this study was therefore to characterize the locomotor muscle adaptations to EET in patients with severe COPD, and compare them with adaptations gained through conventional concentric ergometer training (CET). Male patients were randomized to either EET (
= 8) or CET (
= 7) for 10 weeks and matched for heart rate intensity. EET patients trained on average at a workload that was three times that of CET, at a lower perception of leg fatigue and dyspnea. EET led to increases in isometric peak strength and relative thigh mass (
< 0.01) whereas CET had no such effect. However, EET did not result in fiber hypertrophy, as morphometric analysis of muscle biopsies showed no increase in mean fiber cross-sectional area (
= 0.82), with variability in the direction and magnitude of fiber-type responses (20% increase in Type 1,
= 0.18; 4% decrease in Type 2a,
= 0.37) compared to CET (26% increase in Type 1,
= 0.04; 15% increase in Type 2a,
= 0.09). EET had no impact on mitochondrial adaptation, as revealed by lack of change in markers of mitochondrial biogenesis, content and respiration, which contrasted to improvements (
< 0.05) within CET muscle. While future study is needed to more definitively determine the effects of EET on fiber hypertrophy and associated underlying molecular signaling pathways in COPD locomotor muscle, our findings promote the implementation of this strategy to improve muscle strength. Furthermore, contrasting mitochondrial adaptations suggest evaluation of a sequential paradigm of eccentric followed by concentric cycling as a means of augmenting the training response and attenuating skeletal muscle dysfunction in patients with advanced COPD.
Low mitochondrial content and oxidative capacity are well-established features of locomotor muscle dysfunction, a prevalent and debilitating systemic occurrence in patients with chronic obstructive ...pulmonary disease (COPD). Although the exact cause is not firmly established, physical inactivity and oxidative stress are among the proposed underlying mechanisms. Here, we assess the impact of COPD pathophysiology on mitochondrial DNA (mtDNA) integrity, biogenesis, and cellular oxidative capacity in locomotor muscle of COPD patients and healthy controls. We hypothesized that the high oxidative stress environment of COPD muscle would yield a higher presence of deletion-containing mtDNA and oxidative-deficient fibers and impaired capacity for mitochondrial biogenesis.
Vastus lateralis biopsies were analyzed from 29 COPD patients and 19 healthy age-matched controls for the presence of mtDNA deletions, levels of oxidatively damaged DNA, mtDNA copy number, and regulators of mitochondrial biogenesis as well the proportion of oxidative-deficient fibers (detected histologically as cytochrome c oxidase-deficient, succinate dehydrogenase positive (COX(-)/SDH(+) )). Additionally, mtDNA copy number and mitochondrial transcription factor A (TFAM) content were measured in laser captured COX(-)SDH(+) and normal single fibers of both COPD and controls.
Compared to controls, COPD muscle exhibited significantly higher levels of oxidatively damaged DNA (8-hydroxy-2-deoxyguanosine (8-OHdG) levels = 387 ± 41 vs. 258 ± 21 pg/mL) and higher prevalence of mtDNA deletions (74 vs. 15 % of subjects in each group), which was accompanied by a higher abundance of oxidative-deficient fibers (8.0 ± 2.1 vs. 1.5 ± 0.4 %). Interestingly, COPD patients with mtDNA deletions had higher levels of 8-OHdG (457 ± 46 pg/mL) and longer smoking history (66.3 ± 7.5 years) than patients without deletions (197 ± 29 pg/mL; 38.0 ± 7.3 years). Transcript levels of regulators of mitochondrial biogenesis and oxidative metabolism were upregulated in COPD compared to controls. However, single fiber analyses of COX(-)/SDH(+) and normal fibers exposed an impairment in mitochondrial biogenesis in COPD; in healthy controls, we detected a marked upregulation of mtDNA copy number and TFAM protein in COX(-)/SDH(+) compared to normal fibers, reflecting the expected compensatory attempt by the oxidative-deficient cells to increase energy levels; in contrast, they were similar between COX(-)/SDH(+) and normal fibers in COPD patients. Taken together, these findings suggest that although the signaling factors regulating mitochondrial biogenesis are increased in COPD muscle, impairment in the translation of these signals prevents the restoration of normal oxidative capacity.
Single fiber analyses provide the first substantive evidence that low muscle oxidative capacity in COPD cannot be explained by physical inactivity alone and is likely driven by the disease pathophysiology.
Abstract only
Despite age‐related loss of functioning motor units (MU), masters athletes (MA) in their 7th decade of life retained more MUs than recreationally active controls in the tibialis ...anterior (TA). It is unknown whether MAs beyond the 7th decade would show similar results. The purpose was to estimate the number of functioning MUs (MUNE) in world‐class, older male (n=4; 80 ± 5 y) and female (n=4; 80 ± 8 y) MAs ranging from 75 to 93 y. A maximal compound muscle action potential (CMAP) was recorded from the TA. Decomposition‐enhanced spike‐triggered averaging was used to analyze surface and intramuscular EMG from the TA during voluntary dorsiflexion contractions in order to derive a MUNE. For both sexes, CMAP was ~43% greater than previously reported in age‐matched normative data in males (6.7 ± 0.9 vs 4.7 ± 1.0 mV) (McNeil et al 2005), which may suggest a maintenance of excitable muscle mass in MAs. Mean surface MU potential (SMUP) size was similar between female MAs (64.3 ± 8.1 μV ) and normative data (78.2 ± 19.3 μV ), whereas male MAs had greater SMUP size than either group (138.0 ± 58.5 μV ). The resultant MUNE for female and male MAs was 100 ± 9 and 55 ± 24 MUs, respectively (p<0.05), with females but not males being higher than age norms. These preliminary results may indicate a sex‐specific protection of MUs in elite MAs >; 75 y of age, where MAs of both sexes may better maintain excitable muscle mass with aging.
Supported by: CIHR (MOP 84408 to T.T.)
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