Cisplatin, a platinum-based drug extensively utilized in chemotherapy, is effective in treating a variety of cancer forms. Clinical studies have shown that cisplatin triggers muscle wasting and dysfunction, which significantly impacts the clinical prognosis of cancer patients. Additionally, recent research revealed that pyroptosis, a highly inflammatory cell-death, mediates muscle wasting. However, its role in cisplatin-induced skeletal muscle toxicity remains unclear. Therefore, we hypothesized that cisplatin induces myotoxicity and causes adverse skeletal muscle remodeling through pyroptosis. In this study, C57BL/6 mice (10±2 weeks old) were divided into two groups: Control(saline) and Cisplatin (cisplatin). Saline and Cisplatin were respectively administered via intraperitoneal injection (i.p.) at 2.3mg/kg body weight (BW) for 5 consecutive days (first cycle), followed by 5 days of rest, and then another 5 consecutive days (second cycle), making it a total of 10 injections and a cumulative dose of 23 mg/kg BW. At day 29 (D29), the muscle function was assessed by subjecting the mice to grip force tests and weight tests. Gastrocnemius muscle tissues from sacrificed mice were collected for histological analysis. Further analysis for protein expression of pyroptosis-associated markers (TLR4, NLRP3, Caspase-1, IL-1β, IL-18, and GSDMD) was performed using immunohistochemistry and western blotting. The stimulation of TLR4 leads to the formation of the NLRP3 inflammasome which initiates the activation of Caspase-1, Il-1β and IL-18, along with the executioner of pyroptosis, GSDMD. Our data revealed that cisplatin-treatment significantly (P

Introduction: Chronic obstructive pulmonary disease (COPD) is one of the most common chronic respiratory diseases. Impairments in exercise capacity, kinesiology and skeletal muscle function are well established in these patients. Recently presented data also suggests impairments in postural balance and increased risk of falls in patients with COPD. The aim of this study is to examine postural balance functions in a group of patients and compare the results with a control group. Methods: Twelve patients (the average age 65,6 ± 7,1, 5 women, 7 men) with COPD hospitalized at the Pulmonary Clinic at the Faculty Hospital, Prague Motol and 10 healthy control subjects (the average age 58,6 ± 5,2, 7 women, 3 men) participated in this study. Participants were measured by The Activities-specific Balance Confidence Scale (ABC) and The Balance Evaluation Systems Test (BESTest). Results: COPD patients scored significantly worse (0,0099, p < 0,05) on the ABC scale total score compared to healthy controls, 78,38 ± 21,14 for COPD versus 97,78 ± 3,88 for controls. The total score and the six subsystem categories score of the BESTest were lower in COPD patients, but not significantly, compared to controls. Conclusion: Patients with COPD showed a lower degree of balance confidence and postural balance functions....

Skeletal muscle dysfunction in chronic obstructive pulmonary disease (COPD) is a condition in which peripheral skeletal muscle undergoes myopathic changes which impair muscle function, limit physical performance, and can lead to significant disability. While the etiology of the dysfunction is unknown, this study was conducted to test the hypothesis that chronic hypoxemia leads to alterations in oxygen transport and muscle function. A primary objective was to validate elastase-induced emphysema in rats as an animal model of skeletal muscle dysfunction in COPD.Arterial blood gases were used to determine the severity of hypoxemia and sodium dodecyl sulfate- polyacrylamide gel electrophoresis was used to determine the proportions of myosin heavy chain isoforms I, IIa, IIx, and IIb. Measures of microvascular oxygenation and blood flow in the spinotrapezius muscle allowed for determination of both convective and diffusive oxygen supply to the muscle, as well as calculation of muscle oxygen consumption at rest and during electrically stimulated three-minute muscle contractions. Muscle performance measures included peak force, force-time integral, and fatigue index. Due to a presumed rat respiratory virus, which likely resulted in the control group being nearly as hypoxemic as the elastase-induced emphysema group, this study was not able to definitively test the hypothesis that chronic hypoxemia leads to both a diminished supply and demand of oxygen in skeletal muscle. Although many of the results of the present study were not statistically significant, they exhibited consistent trends over time and are likely of physiological significance. All measures of muscle performance were lower in the emphysema group. In addition, spinotrapezius muscle oxygen consumption and blood flow were lower in the emphysema group. The addition of supplemental oxygen during isolated, small-muscle mass exercise did increase the force-time integral by ~18% in both groups, suggesting that muscle work in these hypoxemic animals may be limited by oxygen supply. Thus, the data on muscle fiber type, oxygen consumption and muscle performance suggest that elastase-induced emphysema in rats leads to a similar skeletal muscle dysfunction that is observed in humans with COPD, and indicates that it is a valid animal model of skeletal muscle dysfunction in COPD.

Nous ne sommes plus autorisés à parler de la BPCO comme d'une simple maladie respiratoire mais plutôt comme une maladie générale. Parmi les atteintes systémiques, la dysfonction musculaire apparaît comme un facteur clé dans la physiopathologie de la BPCO car elle domine l'évolution de la maladie. Par ailleurs, le mystère autour de l'origine exacte de cette dysfonction reste encore entier. Il est maintenant bien établi qu'au cours des épisodes d'exacerbations, la dysfonction musculaire atteint son paroxysme, de plus en absence d'accompagnement musculaire spécifique la récupération est quasi nulle. Ainsi, les objectifs de ce travail de thèse ont étés la compréhension des mécanismes impliqués, d'une part, dans la dysfonction musculaire périphérique des patients BPCO stables et instables (après épisode d'exacerbation) et, d'autre part, dans l'amélioration de la fonction musculaire après différents programmes de réentraînements à l'effort. Dans le cadre de notre première étude, nous avons rapporté que l'oxydation des protéines, plus particulièrement les protéines mitochondriales était plus élevée dans le quadriceps des patients avec une BPCO stable. De plus, nous avons montré que les épisodes d'exacerbations sont associés à une augmentation de l'oxydation des protéines, au niveau mitochondriales et contractiles, corrélée à une dysfonction musculaire. Dans un second temps, nous avons envisagé un réentrainement par électrostimulation chez les patients en cours d'exacerbation et un réentrainement individualisé au seuil ventilatoire (intensité modérée) pour les patients cliniquement stables. Nos résultats indiquent que les deux programmes d'entraînement proposés préviennent le stress oxydant musculaire et améliorent la fonction musculaire périphérique chez les patients BPCO. Cependant, les adaptations mitochondriales restent limitées chez les patients BPCO stables comparativement aux sujets contrôles. En conclusion, nos résultats montrent que les protéines contractiles et mitochondriales sont la cible d'une augmentation du stress oxydant musculaire particulièrement au cours d'une exacerbation. Par ailleurs, des programmes de réentraînement adaptés à la sévérité de la fonction musculaire préviennent les dommages liés au stress oxydant musculaire et contribuent à l'amélioration de la fonction musculaire périphérique. Ainsi, nous pensons que nos résultats pourront probablement favoriser l'amélioration de la prescription du réentraînement à l'effort chez les patients BPCO. / We are no longer allowed to consider COPD as a simple respiratory disease but rather as a systemic disease. Among the systemic effects, muscle dysfunction appears to be a key factor in the pathogenesis of COPD because it strongly influences how the disease will progress. However, the exact origin of muscle dysfunction is still unknown. It is acknowledged that during COPD exacerbations muscle dysfunction is worsened and that, in the absence of post-exacerbation muscle training, recovery is slow and partial. Thus, the objectives of this thesis were first to try to understand the cellular mechanisms involved in the peripheral muscle dysfunction in patients with stable and unstable (after exacerbations) COPD and, then, to assess different programs of physical training to improve muscle function in such patients.Concerning the identification of the mechanisms underlying peripheral muscle dysfunction, we found that protein oxidation, particularly mitochondrial protein oxidation, is higher in the quadriceps of patients with stable COPD than in control subjects. In addition, we have shown that COPD exacerbations are associated with increased muscle oxidative damage of mitochondrial and contractile proteins that is correlated with the level of muscle dysfunction. We then assessed a training protocol using neuromuscular electrostimulation for patients during COPD exacerbation and a training program of moderate intensity (ventilatory threshold) for clinically stable patients. Our results indicate that the two training programs prevent oxidative stress and improve muscle function in COPD patients. However, mitochondrial adaptation is limited in patients with stable COPD compared with controls. In conclusion, our results show that contractile and mitochondrial proteins are the target of increased oxidative stress particularly during COPD exacerbation. However, training programs tailored to the severity of muscle dysfunction can prevent further oxidative damage and contribute to improving muscle function. Our findings might help improving the choice of training programs for patients with COPD.

Background About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed-205) in HFpEF and to describe molecular changes elicited by MyoMed-205. - Methods Twenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (healthy) and obese rats as controls. LV (left ventricle) unction was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity. - Results By week 32, untreated obese rats had normal LV ejection fraction but augmented E/e′ ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1. - Conclusions MyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.

No description available.

Purpose To evaluate the pelvic floor health knowledge base and presence of pelvic floor dysfunction (PFD) in women working in an office environment, and whether this knowledge significantly increases following a pelvic floor health education session and a re-education session. To assess whether this knowledge-acquisition leads to significant decrease in PFD. Participants Female volunteers (N=161), ages 18-69 years, were randomly allocated to Groups A, B or C. Methods Online surveys were completed by all groups on three occasions and included validated tools (Prolapse and Incontinence Knowledge Quiz, Pelvic Floor Distress Inventory-20, Pelvic Floor Impact Questionnaire-7) plus sexual function and pelvic floor muscle (PFM) exercise items. On completion of the baseline survey, an education session was given to Groups A and B only (Group C represented the controls). Following this, all participants completed the second survey. Two months later, to allow time for efficacy for the PFM exercises, a re-education presentation was given to Group A only, followed by the final survey administered to all. Analysis Of the 161 volunteers, 16 failed to complete all study requirements, leaving 145 questionnaires (Groups A and B n=48, Group C n=49) available for analysis using ANOVA and Descriptive Analysis. Results The knowledge base of the participants receiving the education showed highly significant improvement compared to the control group, and again for those receiving the re-education session. Although only 14% stated that they had PFD, the surveys revealed that 96% of the participants had PFD. The groups receiving the PFM exercise education and strategies to encourage healthier bladder and bowel habits showed significant decrease in PFD symptoms and increase in QoL. Education was successful in producing highly significant increases in knowledge, importance and commitment toward PFM exercise. Conclusion This study is unique as it evaluated pelvic floor health knowledge and presence of PFD of presumably healthy women within an office setting in contrast to patients seeking PFD medical attention. While further research is required, it is clear that low pelvic floor health knowledge was associated with high prevalence of PFD. Further, as knowledge/awareness significantly increased following education, so did QoL, while PFD significantly decreased.

Purpose To evaluate the pelvic floor health knowledge base and presence of pelvic floor dysfunction (PFD) in women working in an office environment, and whether this knowledge significantly increases following a pelvic floor health education session and a re-education session. To assess whether this knowledge-acquisition leads to significant decrease in PFD. Participants Female volunteers (N=161), ages 18-69 years, were randomly allocated to Groups A, B or C. Methods Online surveys were completed by all groups on three occasions and included validated tools (Prolapse and Incontinence Knowledge Quiz, Pelvic Floor Distress Inventory-20, Pelvic Floor Impact Questionnaire-7) plus sexual function and pelvic floor muscle (PFM) exercise items. On completion of the baseline survey, an education session was given to Groups A and B only (Group C represented the controls). Following this, all participants completed the second survey. Two months later, to allow time for efficacy for the PFM exercises, a re-education presentation was given to Group A only, followed by the final survey administered to all. Analysis Of the 161 volunteers, 16 failed to complete all study requirements, leaving 145 questionnaires (Groups A and B n=48, Group C n=49) available for analysis using ANOVA and Descriptive Analysis. Results The knowledge base of the participants receiving the education showed highly significant improvement compared to the control group, and again for those receiving the re-education session. Although only 14% stated that they had PFD, the surveys revealed that 96% of the participants had PFD. The groups receiving the PFM exercise education and strategies to encourage healthier bladder and bowel habits showed significant decrease in PFD symptoms and increase in QoL. Education was successful in producing highly significant increases in knowledge, importance and commitment toward PFM exercise. Conclusion This study is unique as it evaluated pelvic floor health knowledge and presence of PFD of presumably healthy women within an office setting in contrast to patients seeking PFD medical attention. While further research is required, it is clear that low pelvic floor health knowledge was associated with high prevalence of PFD. Further, as knowledge/awareness significantly increased following education, so did QoL, while PFD significantly decreased.