Mitochondrial dysfunction is implicated in skeletal muscle atrophy and dysfunction with aging, with strong support for an increased mitochondrial‐mediated apoptosis in sedentary rodent models. ...Whether this applies to aged human muscle is unknown, nor is it clear whether these changes are caused by sedentary behavior. Thus, we examined mitochondrial function respiration, reactive oxygen species (ROS) emission, and calcium retention capacity (CRC) in permeabilized myofibers obtained from vastus lateralis muscle biopsies of healthy physically active young (23.7±2.7 yr; mean±sd) and older (71.2±4.9 yr) men. Although mitochondrial ROS and maximal respiratory capacity were unaffected, the acceptor control ratio was reduced by 18% with aging, suggesting mild uncoupling of oxidative phosphorylation. CRC was reduced by 50% with aging, indicating sensitization of the mitochondrial permeability transition pore (mPTP) to apoptosis. Consistent with the mPTP sensitization, older muscles showed a 3‐fold greater fraction of endonuclease G (a mitochondrial proapoptotic factor)‐positive myonuclei. Aged muscles also had lower mitophagic potential, based on a 43% reduction in Parkin to the voltage‐dependent anion channel (VDAC) protein ratio. Collectively, these results show that mitochondrial‐mediated apoptotic signaling is increased in older human muscle and suggest that accumulation of dysfunctional mitochondria with exaggerated apoptotic sensitivity is due to impaired mitophagy.—Gouspillou, G., Sgarioto, N., Kapchinsky, S., Purves‐Smith, F., Norris, B., Pion, C. H., Barbat‐Artigas, S., Lemieux, R, Taivassalo, T., Morais, J. A., Aubertin‐Leheudre, M., Hepple, R. T. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 28, 28–1621 (1633). www.fasebj.org
•Muscle couplings are delayed in iSCI individuals.•Proximal and posterior couplings are absent or greatly decreased after an iSCI.•These results may lead to therapies based on specific muscular ...couplings.
Postural strategies are enabled by rapid muscle activation sequences to prevent a fall. Intralimb muscular couplings underlie these postural strategies are likely impaired after incomplete spinal cord injury (iSCI), leading to inappropriate postural reactions and increased fall risk; yet, the nature of these changes is unknown.
Identify changes occurring in intralimb coupling following a perturbation in individuals with iSCI.
Ten men with iSCI and eight age-matched controls (CTRL) stood on a force-platform that was randomly tilted forward or backward. Electromyographic (EMG) activity of the lower limb muscles was recorded, and coactivation or simultaneous facilitation/suppression between pairs of muscles was analyzed. Onset and duration of coupling latency, intralimb coupling delay, and amplitude ratios were measured in the distal (soleus SOL/tibialis anterior TA), proximal (biceps femoris BF/vastus lateralis VL), anterior (TA-VL), and posterior (SOL-BF) muscle couplings.
In forward tilt, the main coupling was TA-SOL co-contraction for both groups, but the latency was longer and the duration shorter in SCI participants. In backward tilt, the TA-VL co-activation was the main coupling in CTRL (88 %), although it was also expressed by 60 % of SCI participant with a delayed latency. The facilitation/suppression of TA-SOL was the main coupling in SCI group (80 % vs 63 % in CTRL). Delayed coupling latencies were more pronounced in individuals with cervical iSCI and were correlated with the strength of lower limbs.
Similar muscular couplings are present in both groups but are delayed, which might contribute to postural reaction deficits in individuals with iSCI.
The vestibular system is essential to produce adequate postural responses enabling voluntary movement. However, how the vestibular system influences corticospinal output during postural tasks is ...still unknown. Here, we examined the modulation exerted by the vestibular system on corticospinal output during standing. Healthy subjects (n = 25) maintained quiet standing, head facing forward with eyes closed. Galvanic vestibular stimulation (GVS) was applied bipolarly and binaurally at different delays prior to transcranial magnetic stimulation (TMS) which triggered motor evoked potentials (MEPs). With the cathode right/anode left configuration, MEPs in right Soleus (SOL) muscle were significantly suppressed when GVS was applied at ISI = 40 and 130ms before TMS. With the anode right/cathode left configuration, no significant changes were observed. Changes in the MEP amplitude were then compared to changes in the ongoing EMG when GVS was applied alone. Only the decrease in MEP amplitude at ISI = 40ms occurred without change in the ongoing EMG, suggesting that modulation occurred at a premotoneuronal level. We further investigated whether vestibular modulation could occur at the motor cortex level by assessing changes in the direct corticospinal pathways using the short-latency facilitation of the SOL Hoffmann reflex (H-reflex) by TMS. None of the observed modulation occurred at the level of motor cortex. Finally, using the long-latency facilitation of the SOL H-reflex, we were able to confirm that the suppression of MEP at ISI = 40ms occurred at a premotoneuronal level. The data indicate that vestibular signals modulate corticospinal output to SOL at both premotoneuronal and motoneuronal levels during standing.
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.
Abstract
Reduced mobility and physical independence of elders has emerged as a major clinical and public health priority with extended life expectancy. The impact of the neuromuscular function on ...muscle activity and properties has emerged as a critical factor influencing the progress and outcome of muscle changes with aging. However, very little is known about the neuromuscular junctions (NMJs) in humans, in part due to technical constraints limiting the access to healthy, fresh neuromuscular tissue. Here, we describe a method, called Biopsy using Electrostimulation for Enhanced NMJ Sampling (BeeNMJs) that improves the outcome of muscle biopsies. We used local cutaneous stimulation to identify the area enriched with NMJs for each participant at the right Vastus lateralis (VL). The needle biopsy was then performed in proximity of that point. The BeeNMJs procedure was safe for the participants. We observed NMJs in 53.3% of biopsies in comparison with only 16.7% using the traditional method. Furthermore, we observed an average of 30.13 NMJs per sample compared to only 2.33 for the traditional method. Importantly, high-quality neuromuscular material was obtained whereby pre-, postsynaptic, and glial elements were routinely labeled, simultaneously with myosin heavy chain type I. The BeeNMJs approach will facilitate studies of NMJs, particularly in human disease or aging process.
Divergent conclusions emerge from the literature regarding the relationship between muscle quality (defined as muscle strength per unit of muscle mass) and physical function. These contrasted results ...may be due to the influence of factors such as age, obesity, and muscle mass itself. Consequently, the aim of the present study was to explore the role of these factors in the relationship between muscle quality (MQ) and physical function.
Data are from 312 individuals (97 men and 215 women) aged 50 years and older. Body composition (dual energy X-ray absorptiometry) and knee extension strength of the right leg (1 repetition maximum) were assessed. Appendicular lean body mass index (AppLBMI) and MQ (knee extension strength /right leg lean mass) were calculated. A composite score of physical function was created based on the timed up-and-go, alternate step, sit-to-stand, and balance tests.
MQ was significantly associated with physical function when AppLBMI (β = 0.179; P = .004) and body mass index (BMI) (β = 0.178; P = .003), but not age (β = 0.065; P = .26), were included in regression analysis. AppLBMI (β = 0.221; P < .001), BMI (β = 0.234; P < .001), and age (β = 0.134; P = .018) significantly interacted with MQ to determine physical function.
Our results show that muscle mass, obesity, and age influence the relationship between MQ and physical function, suggesting that these factors should be taken into account when interpreting MQ. Even so, higher levels of MQ were associated with higher physical function scores. Nutritional and physical activity interventions may be designed in this regard.
Individuals with incomplete spinal cord injury (iSCI) show altered postural reactions leading to increased risk of falls. To investigate neural correlates underlying this deficit, we assessed the ...modulation pattern of the Soleus H-reflex in iSCI individuals following unexpected perturbations of a base of support. Ten men with iSCI (AIS D) and 8 age-matched controls (CTRL) stood on a force-platform randomly tilted forward or backward. The center of pressure (CoP) excursion, 95% confidence ellipse area and electromyographic (EMG) activity of the Soleus (SOL) and Tibialis Anterior (TA) muscles were analyzed. SOL H-reflex amplitude was assessed by stimulating the tibial nerve prior to and at 100, 150 and 200 ms following perturbation onset. Although SOL and TA short-latency EMG responses were comparable in both groups, long-latency EMG responses occurred later in the iSCI group for both directions: during backward tilt, a decrease in H-reflex amplitude was observed at all stimulus timings post-tilt in CTRL, but only at 200 ms in iSCI. The decrease in H-reflex amplitude was smaller in iSCI participants. During forward tilt, an increase in H-reflex amplitude was observed at 150 and 200 ms in the CTRL group, but no increase was observed in the iSCI group. Decreased and delayed SOL H-reflex amplitude modulation in the iSCI group accompanied impaired balance control as assessed clinically with the Berg Balance Scale and biomechanically through CoP displacement. Overall, delayed and reduced spinal reflex processing may contribute to impaired balance control in people with iSCI.
Aging leads to a loss of muscle strength and functional capacity likely resulting from a combination of neural and muscle alterations. The aim of this study was to identify possible disparities in ...muscle strength and force development profiles in high- and low-functioning elderly men and to investigate muscular and neurophysiological factors that could explain the differences.
Sixty community-dwelling men in good general health were divided in two groups based on a functional capacity (FC) z-score derived from 6 tests of the Short Physical Performance Battery and Senior Fitness Test (Normal and fast 4m-walk tests, normal and fast Timed-up and go, chair and stair tests). Extensor strength of the lower limbs (LL) was obtained for concentric (CLES) contraction and combined with lean masses of LL (LLLM) to yield concentric (CLES/LLLM) index. Similarly, extensor strength of the right Quadriceps Femoris (IKES) was obtained during maximal voluntary isometric contraction (MVC) and combined with right thigh lean mass (rTLM) to produce an isometric strength (IKES/rTLM) index. A muscular profile was obtained from: ascending and descending force slopes during the MVC; Vastus Lateralis (VL) muscle twitches parameters (amplitude, contraction and ½ relaxation times); the knee joint velocity (KV) as well as integrated EMG (iEMG) were determined for a sit-to-stand functional evaluation; muscle phenotype. A neurophysiological profile was established from: the spinal excitability (Hmax/Mmax ratio); motoneuron conduction velocity (CV); the completeness of muscle activation (% of force reserve), median power frequency (MPF) and mean amplitude (MA) of the VL EMG signal during MVC.
Coincidently, age did not differ between groups. Strength and force indices, descending force slopes for MVC, KV and iEMG during the sit-to-stand evaluation and FC parameters were all significantly (p<0.05) lower in the LoFC group than in the HiFC group. In contrast, no difference was observed between groups in: LLLM and rTLM, Hmax/Mmax ratio, CV, twitch parameters and muscle phenotype.
The lower concentric and isometric strengths found in the LoFC group could not be accounted for by muscular factors. Similarly, peripheral nervous systems alterations could not explain group differences. It can be suggested that modifications within the central nervous system may be responsible for the differences in the functional status of healthy elderly individuals. Finally, more complex and demanding tasks, such as those requiring greater intensity or coordination, may further clarify how healthy elderly individuals with low and high functional capacities differ.
•Low-functioning elderly men had difficulty initiating a functional movement•Functional level was unrelated to muscular factors•Slower maximal force release is associated with low functional level•Central nervous system inhibition was greater for low-functioning elderly men
Abstract
Cannabis is the main illicit psychoactive substance used by pregnant women in France. The aim of the present national survey was to describe adverse events (AEs) of recreational cannabis use ...during pregnancy reported to the French Addictovigilance Network (FAN). Spontaneous reports (SRs) of AEs related to recreational cannabis use during pregnancy were collected by the FAN between 01/01/2011 and 31/01/2021 (excluding cannabidiol and synthetic cannabinoids). Over the study period, 160 SRs involved cannabis use alone or in association with tobacco (59% of all SRs) which increased. Among the 175 maternal AEs, the most commons were psychiatric AEs experienced by 96 (64.9%) women, in particular cannabis use disorders (n = 89, 60.1%), dependence (n = 54, 36.5%) and abuse (n = 21, 14.2%). Among the 57 fetal AEs, the most common were heart rhythm disorders that affected 25 (16.9%) fetuses and intrauterine growth restriction (IUGR) (n = 20, 13.5%). Among the 140 neonatal AEs, the most common were IUGR experienced by 39 (26.3%) newborns and prematurity (n = 32, 21.6%). Twelve cases of congenital malformations were observed and 4 intrauterine/neonatal deaths. Furthermore, some of these AEs (n = 13) were unexpected. Cannabis use during pregnancy has problematic consequences for both mothers and infants who need close monitoring.
Background
The exact impact of ageing on skeletal muscle phenotype and mitochondrial and lipid content remains controversial, probably because physical activity, which greatly influences muscle ...physiology, is rarely accounted for. The present study was therefore designed to investigate the effects of ageing, physical activity, and pre‐frailty on skeletal muscle phenotype, and mitochondrial and intramyocellular lipid content in men.
Methods
Recreationally active young adult (20–30 yo; YA); active (ACT) and sedentary (SED) middle‐age (50–65 yo; MA‐ACT and MA‐SED); and older (65 + yo; 65 + ACT and 65 + SED) and pre‐frail older (65 + PF) men were recruited. Muscle biopsies from the vastus lateralis were collected to assess, on muscle cross sections, muscle phenotype (using myosin heavy chain isoforms immunolabelling), the fibre type‐specific content of mitochondria (by quantifying the succinate dehydrogenase stain intensity), and the fibre type‐specific lipid content (by quantifying the Oil Red O stain intensity).
Results
Only 65 + SED and 65 + PF displayed significantly lower overall and type IIa fibre sizes vs. YA. 65 + SED displayed a lower type IIa fibre proportion vs. YA. MA‐SED and 65 + SED displayed a higher hybrid type IIa/IIx fibre proportion vs. YA. Sedentary and pre‐frail, but not active, men displayed lower mitochondrial content irrespective of fibre type vs. YA. 65 + SED, but not 65 + ACT, displayed a higher lipid content in type I fibres vs. YA. Finally, mitochondrial content, but not lipid content, was positively correlated with indices of muscle function, functional capacity, and insulin sensitivity across all subjects.
Conclusions
Taken altogether, our results indicate that ageing in sedentary men is associated with (i) complex changes in muscle phenotype preferentially affecting type IIa fibres; (ii) a decline in mitochondrial content affecting all fibre types; and (iii) an increase in lipid content in type I fibres. They also indicate that physical activity partially protects from the effects of ageing on muscle phenotype, mitochondrial content, and lipid accumulation. No skeletal specific muscle phenotype of pre‐frailty was observed.
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