Background
This two‐part study explored the safety, feasibility, and efficacy of a mild–moderate resistance isometric leg exercise program in ambulatory boys with Duchenne muscular dystrophy (DMD).
...Methods
First, we used a dose escalation paradigm with varying intensity and frequency of leg isometric exercise to determine the dose response and safety in 10 boys. Second, we examined safety and feasibility of a 12‐wk in‐home, remotely supervised, mild–moderate intensity strengthening program in eight boys. Safety measures included T2 MRI, creatine kinase levels, and pain. Peak strength and function (time to ascend/descend four stairs) were also measured.
Results
Dose‐escalation revealed no signs of muscle damage. Seven of the eight boys completed the 12‐wk in‐home program with a compliance of 84.9%, no signs of muscle damage, and improvements in strength (knee extensors P < .01; knee flexors P < .05) and function (descending steps P < .05).
Conclusions
An in‐home, mild–moderate intensity leg exercise program is safe with potential to positively impact both strength and function in ambulatory boys with DMD.
•ECC achieved safety profile and superiority on isometric QPT compared to CON training.•ECC training patients have experienced a lower sensation of dyspnea.•ECC training could be used as an adjunct ...exercise modality for advanced COPD.
To compare eccentric (ECC) and conventional concentric (CON) cycle training on quadriceps muscle strength in advanced COPD. Secondary objective was to assess functional capacity.
A parallel-group, assessor-blind, randomized trial was conducted. Severe COPD patients were randomized to either an ECC (n = 13) or CON (n = 11) cycling program for 30-min, 3 times/week for 10 weeks. ECC group trained at ∼4-fold higher power than the CON group at similar relative heart rate intensity.
Isometric and isokinetic quadriceps peak torque improved after ECC but not CON; between group difference was significant for isometric peak muscle force (p < 0.05). Peak cycling power and endurance time increased in both groups (p < 0.05). Dyspnea at peak cycling power improved only after ECC training (p < 0.05). Sensory intensity ratings of dyspnea and leg fatigue were significantly lower (p < 0.05) during ECC compared with CON at equivalent relative heart rate intensities.
ECC could be an effective alternative and/or adjunct modality to pulmonary rehabilitation in severely ventilatory limited COPD patients.
Our group has shown a greater number of functioning motor units (MU) in a cohort of highly active older (∼65 yr) masters runners relative to age-matched controls. Because of the precipitous loss in ...the number of functioning MUs in the eighth and ninth decades of life it is unknown whether older world class octogenarian masters athletes (MA) would also have greater numbers of functioning MUs compared with age-matched controls. We measured MU numbers and neuromuscular transmission stability in the tibialis anterior of world champion MAs (∼80 yr) and compared the values with healthy age-matched controls (∼80 yr). Decomposition-enhanced spike-triggered averaging was used to collect surface and intramuscular electromyography signals during dorsiflexion at ∼25% of maximum voluntary isometric contraction. Near fiber (NF) MU potential analysis was used to assess neuromuscular transmission stability. For the MAs compared with age-matched controls, the amount of excitable muscle mass (compound muscle action potential) was 14% greater (P < 0.05), there was a trend (P = 0.07) toward a 27% smaller surface-detected MU potential representative of less collateral reinnervation, and 28% more functioning MUs (P < 0.05). Additionally, the MAs had greater MU neuromuscular stability than the controls, as indicated by lower NF jitter and jiggle values (P < 0.05). These results demonstrate that high-performing octogenarians better maintain neuromuscular stability of the MU and mitigate the loss of MUs associated with aging well into the later decades of life during which time the loss of muscle mass and strength becomes functionally relevant. Future studies may identify the concomitant roles genetics and exercise play in neuroprotection.
Summary
Mitochondria regulate cellular bioenergetics and apoptosis and have been implicated in aging. However, it remains unclear whether age‐related loss of muscle mass, known as sarcopenia, is ...associated with abnormal mitochondrial function. Two technically different approaches have mainly been used to measure mitochondrial function: isolated mitochondria and permeabilized myofiber bundles, but the reliability of these measures in the context of sarcopenia has not been systematically assessed before. A key difference between these approaches is that contrary to isolated mitochondria, permeabilized bundles contain the totality of fiber mitochondria where normal mitochondrial morphology and intracellular interactions are preserved. Using the gastrocnemius muscle from young adult and senescent rats, we show marked effects of aging on three primary indices of mitochondrial function (respiration, H2O2 emission, sensitivity of permeability transition pore to Ca2+) when measured in isolated mitochondria, but to a much lesser degree when measured in permeabilized bundles. Our results clearly demonstrate that mitochondrial isolation procedures typically employed to study aged muscles expose functional impairments not seen in situ. We conclude that aging is associated with more modest changes in mitochondrial function in sarcopenic muscle than suggested previously from isolated organelle studies.
Human skeletal muscle respiratory chain defects restrict the ability of working muscle to extract oxygen from blood, and result in a hyperkinetic circulation during exercise in which oxygen delivery ...is excessive relative to oxygen uptake and oxygen levels within contracting muscle are abnormally high. To investigate the role of the muscle microcirculation in this anomalous circulatory response and possible implications for the regulation of muscle angiogenesis, we assessed muscle oxidative capacity during cycle exercise and determined capillary levels and distribution and vascular endothelial growth factor expression in quadriceps muscle biopsies in patients with mitochondrial myopathy attributable to heteroplasmic mitochondrial DNA mutations. We found that in patients with mitochondrial myopathy, muscle capillary levels were twice that of sedentary healthy subjects (3.0 ± 0.9% compared with 1.4 ± 0.3%, P < 0.001) despite the fact that oxygen utilization during peak cycle exercise was half that of control subjects (11.1 ± 4.0 ml/kg/min compared with 20.7 ± 7.9 ml/kg/min, P < 0.01); that capillary area was greatest in patients with the most severe muscle oxidative defects and was more than two times higher around muscle fibre segments with defective (i.e. cytochrome oxidase negative/succinic dehydrogenase-positive or 'ragged-red' fibres) compared with more preserved respiratory chain function; and that vascular endothelial growth factor expression paralleled capillary distribution. The increased muscle capillary levels in patients correlated directly (r
2 = 0.68, P < 0.05) with the severity of the mismatch between systemic oxygen delivery (cardiac output) and oxygen utilization during cycle exercise. Our results suggest that capillary growth is increased as a result of impaired muscle oxidative phosphorylation in mitochondrial myopathy, thus promoting increased blood flow to respiration-incompetent muscle fibres and a mismatch between oxygen delivery and utilization during exercise. Furthermore, the finding of high capillary levels despite elevated tissue oxygen levels during exercise in respiration-deficient muscle fibres implies that mitochondrial metabolism activates angiogenesis in skeletal muscle by a mechanism that is independent of hypoxia.
Background
Studies in aging rodent models and elderly men have recognized skeletal muscle denervation as an important factor contributing to age‐related muscle atrophy. This has not yet been assessed ...in octogenarian women, a population that is at a greater risk of becoming physically frail. On this basis we determined the presence of muscle denervation in prefrail/frail elderly women and its contribution to aging muscle phenotypes compared to a population with high function in advanced age, world class octogenarian track and field athletes.
Methods
Muscle biopsies were obtained from vastus lateralis muscle from prefrail/frail elderly women (FE, n=17, 77.9±1.5y), master athletes (MA, n=7, 80.9±2.2y) and young inactive (YI, n=12, 24.0±1.0y) controls, to assess denervation‐induced morphological and transcriptional markers.
Results
The FE group displayed a high abundance of grouped slow fibers, accumulation of very small myofibers, a severe reduction in type IIa to type I size ratio, and an accumulation of neural cell adhesion molecule‐positive myofibers and pyknotic nuclei, consistent with recurring cycles of denervation/reinnervation with a sporadic occurrence of failed reinnervation in prefrail/frail subjects. The MA group exhibited a smaller decline in type IIa/I size ratio, but not attenuated fiber atrophy relative to FE, and this was associated with a higher degree of fiber type I grouping in MA vs FE, suggesting a greater reinnervation of denervated fibers in MA. Consistent with this interpretation, MA had higher mRNA levels of the reinnervation promoting cytokine Fibroblast Growth Factor Binding Protein 1 than FE.
Conclusion
Our results indicate that the muscle of prefrail/frail elderly women undergoes significant neurogenic atrophy, whereas MA exhibit evidence of superior reinnervation capacity that attenuates functional decline with aging by attenuating aging muscle atrophy through better retention of muscle fiber number.
Support or Funding Information
This work was supported by Canadian Institute of Health Research (MOP 125986 and MOP 119583 to R.T. Hepple). Part of the expenses involving older participants was supported by an Internal Grant from the Helen McCall Hutchison Family Foundation of the Montreal General Hospital. V. Sonjak was supported by the Bloomberg Manulife Fellowship. K.J. Jacob was supported by a PhD scholarship from the Fonds de recherche du Quebec – Sante (FRQS).
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Locomotor muscle atrophy develops in patients with chronic obstructive pulmonary disease (COPD) partly because of increased protein degradation by the ubiquitin-proteasome system. It is not known if ...autophagy also contributes to protein degradation.
To investigate whether autophagy is enhanced in locomotor muscles of stable patients with COPD, to quantify autophagy-related gene expression in these muscles, and to identify mechanisms of autophagy induction.
Muscle biopsies were obtained from two cohorts of control subjects and patients with COPD and the numbers of autophagosomes in the vastus lateralis and tibialis anterior muscles, the levels of LC3B protein lipidation, and the expression of autophagy-related genes were measured in the vastus lateralis muscle. To investigate potential pathways that might induce the activation of autophagy, measures were taken of protein kinase B (AKT), mTORC1, and AMPK pathway activation, transcription factor regulation, proteasome activation, and oxidative stress.
Autophagy is enhanced in the locomotor muscles of patients with COPD as shown by significantly higher numbers of autophagosomes in affected muscles as compared with control subjects. Autophagosome number inversely correlates with FEV1. In the vastus lateralis, LC3B protein lipidation is increased by COPD and the expression of autophagy-related gene expressions is up-regulated. LC3B lipidation inversely correlates with thigh cross-sectional area, FEV1, and FEV1/FVC ratio. Enhanced autophagy is associated with activation of the AMPK pathway and FOXO transcription factors, inhibition of the mTORC1 and AKT pathways, and the development of oxidative stress.
Autophagy is significantly enhanced in locomotor muscles of stable patients with COPD. The degree of autophagy correlates with severity of muscle atrophy and lung function impairment.
Introduction
In this study we explored walking activity in a large cohort of boys with Duchenne muscular dystrophy (DMD).
Methods
Step activity (monitored for 7 days), functional ability, and ...strength were quantified in ambulatory boys (5‐12.9 years of age) with DMD and unaffected boys. Ambulatory status was determined 2 years later.
Results
Two to 5 days of activity monitoring predicted weekly step activity (adjusted R2 = 0.80‐0.95). Age comparisons revealed significant declines for step activity with increasing age, and relationships were found between step activity with both function and strength (P < .01). Our regression model predicted 36.5% of the variance in step activity. Those who were still ambulatory after 2 years demonstrated baseline step activity nearly double that of those who were no longer walking 2 years later (P < .01).
Discussion
Step activity for DMD is related to and predictive of functional declines, which may be useful for clinical trials.
New Findings
What is the central question of this study?
Does the combination of a higher neural respiratory drive and greater dynamic mechanical ventilatory constraints during exercise in healthy ...women versus men form the mechanistic basis of sex differences in activity‐related dyspnoea?
What is the main finding and its importance?
Sex differences in activity‐related dyspnoea in health primarily reflected the awareness of a higher neural respiratory drive needed to achieve any given ventilation during exercise in the setting of relatively greater dynamic mechanical ventilatory constraints in women. These findings may have implications for our understanding of the mechanisms of sex differences in exertional dyspnoea in variants of health (e.g. the elderly) and in patients with cardiorespiratory disease.
The purpose of this study was to elucidate the physiological mechanisms of sex differences in exertional dyspnoea. We compared detailed measures of neural respiratory motor drive diaphragmatic EMG (EMGdi) expressed as a percentage of maximal EMGdi (EMGdi%max), breathing pattern, operating lung volumes, dynamic respiratory mechanics tidal oesophageal (Poes,tidal%peak) and transdiaphragmatic pressure swings (Pdi,tidal%peak) expressed as a percentage of their respective peak values and sensory intensity and unpleasantness ratings of dyspnoea during symptom‐limited incremental cycle exercise in healthy young women (n = 25) and men (n = 25). The tidal volume to forced vital capacity ratio (VT%FVC), breathing frequency, EMGdi%max, Poes,tidal%peak, Pdi,tidal%peak and sensory intensity and unpleasantness ratings of dyspnoea were higher, while dynamic inspiratory capacity and inspiratory reserve volume were lower at a standardized absolute ventilation of 55 l min−1 during submaximal exercise in women versus men (all P < 0.05). In contrast, sex had no demonstrable effect on the inter‐relationships between exercise‐induced increases in VT%FVC, EMGdi%max and sensory intensity and unpleasantness ratings of dyspnoea. The results of this study suggest that sex differences in the intensity and unpleasantness of exertional dyspnoea in health are likely to reflect the awareness of a relatively higher neural respiratory motor drive (or EMGdi%max) needed to achieve any given ventilation during exercise in the setting of relatively greater dynamic mechanical constraints on VT expansion in women.
A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal ...muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in
ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis.
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