Key points
Mitochondria are frequently implicated in the ageing of skeletal muscle, although the role of denervation in modulating mitochondrial function in ageing muscle is unknown.
We show that ...increased sensitivity to apoptosis initiation occurs prior to evidence of persistent denervation and is thus a primary mitochondrial defect in ageing muscle worthy of therapeutic targeting.
However, at more advanced age, mitochondrial function changes are markedly impacted by persistent sporadic myofibre denervation, suggesting the mitochondrion may be a less viable therapeutic target.
Experimental denervation modulates mitochondrial function, where changes in both reactive oxygen species (ROS) and sensitivity to permeability transition are implicated in the resultant muscle atrophy. Notably, although denervation occurs sporadically in ageing muscle, its impact on ageing muscle mitochondria is unknown. Because this information has important therapeutic implications concerning targeting the mitochondrion in ageing muscle, we examined mitochondrial function in skeletal muscle from four groups of humans, comprising two active (mean ± SD age: 23.7 ± 2.7 years and 71.2 ± 4.9 years) and two inactive groups (64.8 ± 3.1 years and 82.5 ± 4.8 years), and compared this with a murine model of sporadic denervation. We tested the hypothesis that, although some alterations of mitochondrial function in aged muscle are attributable to a primary organelle defect, mitochondrial dysfunction would be impacted by persistent denervation in advanced age. Both ageing in humans and sporadic denervation in mice increased mitochondrial sensitivity to permeability transition (humans, P = 0.004; mice, P = 0.01). To determine the contribution of sporadic denervation to mitochondrial function, we pharmacologically inhibited the denervation‐induced ROS response. This reduced ROS emission by 60% (P = 0.02) in sporadically denervated mouse muscle, which is similar to that seen in humans older than 75 years (–66%, P = 0.02) but not those younger than 75 years. We conclude that an increased sensitivity to permeability transition is a primary mitochondrial defect in ageing muscle. However, at more advanced age, when muscle atrophy becomes more clinically severe, mitochondrial function changes are markedly impacted by persistent sporadic denervation, making the mitochondrion a less viable therapeutic target.
Key points
Mitochondria are frequently implicated in the ageing of skeletal muscle, although the role of denervation in modulating mitochondrial function in ageing muscle is unknown.
We show that increased sensitivity to apoptosis initiation occurs prior to evidence of persistent denervation and is thus a primary mitochondrial defect in ageing muscle worthy of therapeutic targeting.
However, at more advanced age, mitochondrial function changes are markedly impacted by persistent sporadic myofibre denervation, suggesting the mitochondrion may be a less viable therapeutic target.
Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.
We performed ...muscle biopsies in 15 octogenarian world-class track and field MAs and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mitochondrial DNA (mtDNA) copy number, and proteomics by liquid-chromatography mass spectrometry.
MA exhibited markedly better performance on clinical function tests and greater cross-sectional area of the vastus lateralis muscle. Proteomics analysis revealed marked differences, where most of the ~800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage-dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and that are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA.
We conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with underrepresentation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging.
Funding for this study was provided by operating grants from the Canadian Institutes of Health Research (MOP 84408 to TT and MOP 125986 to RTH). This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA.
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.
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.
The purpose of the present study was to examine changes in
V
O
2peak
,
V
O
2
kinetics and steady-state exercise performance following 4 weeks of participation in recreational sport. Subjects (male
n
... = 8, female
n
= 9) participated in recreational sport (basketball, floor hockey and soccer) four times per week for 4 weeks. Both before and after training,
V
O
2peak
was measured on a cycle ergometer,
V
O
2
kinetics was determined as the average of three transitions to 80 W, and heart rate (HR) and respiratory exchange ratio (RER) were measured during 60 min at a work rate corresponding to 50 % of pre-training
V
O
2peak
. HR was also monitored during all training sessions. After training,
V
O
2peak
was increased in females, but not males, while
V
O
2
kinetics (τ
V
O
2
) were sped in both males and females. HR during constant load exercise was reduced in both males and females, but exercise RER was only reduced in females. Mean HR during participation in sport was higher in males than females and higher during basketball than both floor hockey and soccer. These results demonstrate that training adaptations traditionally associated with endurance exercise can also be obtained through regular participation in recreational sport.
After providing informed consent, participants wore heart rate monitors (Polar Team2 Pro system, Polar, Lachine, QC) during two games of their intramural sport (Soccer, 80 min/game; Frisbee, 40 ...min/game). ...absolute exercise intensity (METs) and energy expenditure (kcal) are impacted by both sex and aerobic fitness suggesting that participation in sport by some populations (sedentary, overweight, clinical, or female populations for example) may not be associated with significant health benefit. Strath S.J., Swartz A.M., Bassett D.R., O'Brien W.L., King G.A., Ainsworth B.E. (2000) Evaluation of heart rate as a method for assessing moderate intensity physical activity.
The purpose of the present study was to examine changes in VO^sub 2peak^, VO2 kinetics and steady-state exercise performance following 4 weeks of participation in recreational sport. Subjects (male n ...= 8, female n = 9) participated in recreational sport (basketball, floor hockey and soccer) four times per week for 4 weeks. Both before and after training, VO^sub 2peak^ was measured on a cycle ergometer, VO2 kinetics was determined as the average of three transitions to 80 W, and heart rate (HR) and respiratory exchange ratio (RER) were measured during 60 min at a work rate corresponding to 50 % of pre-training VO^sub 2peak^. HR was also monitored during all training sessions. After training, VO^sub 2peak^ was increased in females, but not males, while VO2 kinetics (tauVO2) were sped in both males and females. HR during constant load exercise was reduced in both males and females, but exercise RER was only reduced in females. Mean HR during participation in sport was higher in males than females and higher during basketball than both floor hockey and soccer. These results demonstrate that training adaptations traditionally associated with endurance exercise can also be obtained through regular participation in recreational sport.PUBLICATION ABSTRACT
The purpose of the present study was to examine changes in VO sub(2peak), VO sub(2) kinetics and steady-state exercise performance following 4 weeks of participation in recreational sport. Subjects ...(male n = 8, female n = 9) participated in recreational sport (basketball, floor hockey and soccer) four times per week for 4 weeks. Both before and after training, VO sub(2peak) was measured on a cycle ergometer, VO sub(2) kinetics was determined as the average of three transitions to 80 W, and heart rate (HR) and respiratory exchange ratio (RER) were measured during 60 min at a work rate corresponding to 50 % of pre-training VO sub(2peak). HR was also monitored during all training sessions. After training, VO sub(2peak) was increased in females, but not males, while VO sub(2) kinetics ( tau VO sub(2)) were sped in both males and females. HR during constant load exercise was reduced in both males and females, but exercise RER was only reduced in females. Mean HR during participation in sport was higher in males than females and higher during basketball than both floor hockey and soccer. These results demonstrate that training adaptations traditionally associated with endurance exercise can also be obtained through regular participation in recreational sport.
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