Objective
Susceptibility to exertional cramps and rhabdomyolysis in myophosphorylase deficiency (McArdle's disease MD) may lead patients to shun exercise. However, physical inactivity may worsen ...exercise intolerance by further reducing the limited oxidative capacity caused by blocked glycogenolysis. We investigated whether aerobic conditioning can safely improve exercise capacity in MD.
Methods
Eight MD patients (4 men and 4 women; age range, 33–61 years) pedaled a cycle ergometer for 30 to 40 minutes a day, 4 days a week, for 14 weeks, at an intensity corresponding to 60 to 70% of maximal heart rate. We monitored serum creatine kinase levels; changes in peak cycle work, oxygen uptake, and cardiac output; presence and magnitude of a spontaneous and glucose‐induced second wind; and citrate synthase and β‐hydroxyacyl coenzyme A dehydrogenase enzyme activities in quadriceps muscle.
Results
The prescribed exercise program increased average work capacity (36%), oxygen uptake (14%), cardiac output (15%), and citrate synthase and β‐hydroxyacyl coenzyme A dehydrogenase enzyme levels (80 and 62%, respectively) without causing pain or cramping or increasing serum creatine kinase. A spontaneous and glucose‐induced second wind was present and was of similar magnitude in each patient before and after training.
Interpretation
Moderate aerobic exercise is an effective means of improving exercise capacity in MD by increasing circulatory delivery and mitochondrial metabolism of bloodborne fuels. Ann Neurol 2006;59:922‐928
Background
Chronic obstructive pulmonary disease (COPD) patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is ...implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand‐activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke‐induced AHR activation causes adverse muscle impact.
Methods
We used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno‐associated virus‐mediated gene transfer).
Results
Sixteen weeks of tobacco smoke exposure in mice caused muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down‐regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signalling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR‐dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice.
Conclusions
These results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment, and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.
Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this ...clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.
Deficiencies in the activity of complex I (NADH: ubiquinone oxidoreductase) are an important cause of human mitochondrial disease. Complex I is composed of at least 46 structural subunits that are ...encoded in both nuclear and mitochondrial DNA. Enzyme deficiency can result from either impaired catalytic efficiency or an inability to assemble the holoenzyme complex; however, the assembly process remains poorly understood. We have used two-dimensional Blue-Native/SDS gel electrophoresis and a panel of 11 antibodies directed against structural subunits of the enzyme to investigate complex I assembly in the muscle mitochondria from four patients with complex I deficiency caused by either mitochondrial or nuclear gene defects. Immunoblot analyses of second dimension denaturing gels identified seven distinct complex I subcomplexes in the patients studied, five of which could also be detected in nondenaturing gels in the first dimension. Although the abundance of these intermediates varied among the different patients, a common constellation of subcomplexes was observed in all cases. A similar profile of subcomplexes was present in a human/mouse hybrid fibroblast cell line with a severe complex I deficiency due to an almost complete lack of assembly of the holoenzyme complex. The finding that diverse causes of complex I deficiency produce a similar pattern of complex I subcomplexes suggests that these are intermediates in the assembly of the holoenzyme complex. We propose a possible assembly pathway for the complex, which differs significantly from that proposed for Neurospora, the current model for complex I assembly.
The multifactorial functional limitation of COPD increasingly demonstrates the need for an integrated circulatory assessment. In this study cardiac output (Qc) derived from non-inert (CO
2
-RB), ...inert (N
2
O-RB) gas rebreathing approaches and bioimpedance were compared to examine the limitations of currently available non-invasive techniques for exercise Qc determination in patients with chronic lung disease. Thirteen COPD patients (GOLD II-III) completed three constant cycling bouts at 20, 35, and 50% of peak work on two occasions to assess Qc with bioimpedance as well as using CO
2
-RB and N
2
O-RB for all exercise tests. Results showed significantly lower Qc using the N
2
O-RB or end-tidal CO
2
-derived Qc compared to the PaCO
2
-derived CO
2
-RB or the bioimpedance at rest and for all exercise intensities. End-tidal CO
2
-derived values are however not statistically different from those obtained using inert-gas rebreathing. This study show that in COPD patients, CO
2
-rebreathing Qc values obtained using PaCO
2
contents which account for any gas exchange impairment or inadequate gas mixing are similar to those obtained using thoracic bioimpedance. Alternately, the lower values for N
2
O rebreathing derived Qc indicates the inability of this technique to account for gas exchange impairment in the computation of Qc. These findings indicate that the choice of a gas rebreathing technique to measure Qc in patients must be dictated by the ability to include in the derived computations a correction for either gas exchange inadequacies and/or a vascular shunt.
•This is the first study to assess brain rs-FC in older masters athletes (MA).•Higher rs-FC within cognitive regions in MA compared to controls.•Higher rs-FC within motor regions in MA compared to ...controls.•Less rs-FC between cognitive and motor regions in MA compared to controls.•Aging-related rs-FC segregation patterns are attenuated in top-ranked athletes.
Aging is characterized by a decline in physical and cognitive functions, often resulting in decreased quality of life. Physical activity has been suggested to potentially slow down various aspects of the aging process, a theory that has been supported by studies of Masters Athletes (MA). For example, MA usually have better cognitive and physical functions than age-matched sedentary and healthy older adults (OA), making them a valuable model to gain insights into mechanisms that promote physical and cognitive function with aging. The purpose of this study was to identify differences in resting-state functional connectivity (rs-FC) of motor and cognitive regions between MA and OA and determine if these differences in the resting brain are associated with differences in cognitive and physical performance between groups. Fifteen MA (9 males) and 12 age-matched OA (six males) were included. rs-FC images were compared to identify significant between-groups differences in brain connectivity. There was higher connectivity between the cognitive and motor networks for the OA group, whereas the MA group had stronger connectivity between different regions within the same network, both for the cognitive and the motor networks. These results are in line with the literature suggesting that aging reduces the segregation between functional networks and causes regions within the same network to be less strongly connected. High-level physical activity practiced by the MA most likely contributes to attenuating aging-related changes in brain functional connectivity, preserving clearer boundaries between different functional networks, which may ultimately favor maintenance of efficient cognitive and sensorimotor processing.
Key points
Susceptibility to age‐related muscle atrophy relates to the degree of muscle denervation and the capacity of successful reinnervation. However, the specific role of denervation as a ...determinant of the severity of muscle aging between populations with low versus high physical function has not been addressed.
We show that prefrail/frail elderly women exhibited marked features of muscle denervation, whereas world class octogenarian female master athletes showed attenuated indices of denervation and greater reinnervation capacity.
These findings suggest that the difference in age‐related muscle impact between low‐ and high‐functioning elderly women is the robustness of the response to denervation of myofibers.
Ageing muscle degeneration is a key contributor to physical frailty; however, the factors responsible for exacerbated vs. muted ageing muscle impact are largely unknown. Based upon evidence that susceptibility to neurogenic impact is an important determinant of the severity of ageing muscle degeneration, we aimed to determine the presence and extent of denervation in pre‐frail/frail elderly (FE, 77.9 ± 6.2 years) women compared to young physically inactive (YI, 24.0 ± 3.5 years) females, and contrast these findings to high‐functioning world class octogenarian female masters athletes (MA, 80.9 ± 6.6 years). Muscle biopsies from vastus lateralis muscle were obtained from all three groups to assess denervation‐related morphological and transcriptional markers. The FE group displayed marked grouping of slow fibres, accumulation of very small myofibres, a severe reduction in type IIa/I size ratio, highly variable inter‐subject accumulation of neural cell adhesion molecule (NCAM)‐positive myofibres, and an accumulation of pyknotic nuclei, indicative of recurring cycles of denervation/reinnervation and persistent denervation. The MA group exhibited a smaller decline in type IIa/I size ratio and fewer pyknotic nuclei, accompanied by a higher degree of type I fibre grouping and larger fibre group size, suggesting a greater reinnervation of denervated fibres. Consistent with this interpretation, MA had higher mRNA levels of the reinnervation‐promoting cytokine fibroblast growth factor binding protein 1 (FGFBP1) than FE. Our results indicate that the muscle of FE women has significant neurogenic atrophy, whereas MA muscle exhibit superior reinnervation capacity, suggesting that the difference in age‐related muscle impact between low‐ and high‐functioning elderly women is the robustness of the response to denervation of myofibres.
Key points
Susceptibility to age‐related muscle atrophy relates to the degree of muscle denervation and the capacity of successful reinnervation. However, the specific role of denervation as a determinant of the severity of muscle aging between populations with low versus high physical function has not been addressed.
We show that prefrail/frail elderly women exhibited marked features of muscle denervation, whereas world class octogenarian female master athletes showed attenuated indices of denervation and greater reinnervation capacity.
These findings suggest that the difference in age‐related muscle impact between low‐ and high‐functioning elderly women is the robustness of the response to denervation of myofibers.
Abstract only
Introduction
Skeletal muscle mass and function decline with aging, and more precipitously after the age 75 y. To help provide insights into biologically relevant mechanisms for ...preserving muscle mass and function in advanced age, in this study we performed proteomics on skeletal muscle of world class octogenarian track and field athletes in comparison to healthy octogenarian non‐athletes.
Methods
Muscle cross‐sectional area by MRI and a vastus lateralis muscle biopsy were performed in 15 octogenarian world class track and field athletes (8 of whom were world record holders in their discipline at the time of testing) and 14 non‐athlete age‐ and sex‐matched non‐athlete controls. From these subjects, a portion of muscle from a subset of 12 master athletes (MA mean age 81.19 ± 5.1 y) and 12 non‐athlete controls (NA mean age 80.94 ± 4.5 y) was used for liquid‐chromatography mass spectrometry to generate quantitative tandem mass tag proteomics data. In addition, we measured mtDNA copy number, COX/SDH histochemistry to identify respiratory compromised fibers, and Western blot of mitochondrial inner and outer membrane proteins.
Results
Muscle cross‐sectional area was higher in MA. Tandem mass spectrometry identified over 6000 proteins, and significant differences in abundance were found between NA controls and MA for more than 800 proteins. A pathway analysis revealed that pathways involved in mitochondria (e.g., TCA cycle, respiratory electron transport, cristae formation, sirtuins) were higher in MA, while proteins in pathways involved in the spliceosome and nuclear pore were downregulated in MA. Finally, 8 mtDNA‐encoded proteins that were included in the analysis were elevated in MA versus NA. These proteomics data are consistent with phenotypic data showing MA have higher mtDNA copy number, fewer respiratory chain compromised muscle fibers, and an increased ratio of ETC subunits (inner mitochondrial membrane proteins) relative to VDAC (outer mitochondrial membrane protein), suggesting an increase in cristae formation.
Conclusion
Our data underscore that mitochondrial pathways are key to maintaining a high level of physical function in advanced age. With the current study design we cannot determine the degree to which these differences are attributable to the physical activity habits of MA, but it is likely to play a role.
Support or Funding Information
CIHR (MOP 125986 to RTH)
NIA Intramural Research program
Bronchopulmonary dysplasia and the long-term consequences of prematurity are underrecognized entities, unfamiliar to adult clinicians. Well described by the pediatric community, these young adults ...are joining the ranks of a growing population of adults with chronic lung disease.
To describe the quality of life, pulmonary lung function, bronchial hyperresponsiveness, body composition, and trends in physical activity of adults born prematurely, with or without respiratory complications.
Four groups of young adults born in Canada between 1987 and 1993 were enrolled in a cohort study: (1) preterm subjects with no neonatal respiratory complications, (2) preterm subjects with neonatal respiratory distress syndrome, (3) preterm subjects with bronchopulmonary dysplasia, and (4) subjects born at term. The following measurements were compared across the four groups: health-related quality of life, respiratory health, pulmonary function, methacholine challenge test results, and sedentary behavior and physical activity level.
Adult subjects who had bronchopulmonary dysplasia in infancy had mild airflow obstruction (FEV1, 80% predicted; FEV1/FCV ratio, 70) and gas trapping compared with others. They also had less total active energy expenditure and more time spent in sedentary behavior compared with subjects born at term. All preterm groups had a high prevalence of bronchial hyperresponsiveness compared with term subjects.
In a population-derived, cross-sectional study, we confirmed previous reports that adults 21 or 22 years of age who were born prematurely with neonatal bronchopulmonary dysplasia are more likely to have airflow obstruction, bronchial hyperresponsiveness, and pulmonary gas trapping than subjects born prematurely without bronchopulmonary dysplasia or at term. Clinicians who care for adults need to be better informed of the long-term respiratory consequences of premature birth to assist young patients in maintaining lung function and health.
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