A reduced muscle glycogen content and potassium (K+) disturbances across muscle membranes occur concomitantly during repeated intense exercise and together may contribute to skeletal muscle fatigue. ...Therefore, we examined whether raised extracellular K+ concentration (K+o) (4 to 11 mM) interacts with lowered glycogen to reduce force production. Isometric contractions were evoked in isolated mouse soleus muscles (37°C) using direct supramaximal field stimulation. (1) Glycogen declined markedly in non‐fatigued muscle with >2 h exposure in glucose‐free physiological saline compared with control solutions (11 mM glucose), i.e. to <45% control. (2) Severe glycogen depletion was associated with increased 5′‐AMP‐activated protein kinase activity, indicative of metabolic stress. (3) The decline of peak tetanic force at 11 mM K+o was exacerbated from 67% initial at normal glycogen to 22% initial at lowered glycogen. This was due to a higher percentage of inexcitable fibres (71% vs. 43%), yet without greater sarcolemmal depolarisation or smaller amplitude action potentials. (4) Returning glucose while at 11 mM K+o increased both glycogen and force. (5) Exposure to 4 mM K+o glucose‐free solutions (15 min) did not increase fatiguability during repeated tetani; however, after recovery there was a greater force decline at 11 mM K+o at lower than normal glycogen. (6) An important exponential relationship was established between relative peak tetanic force at 11 mM K+o and muscle glycogen content. These findings provide direct evidence of a synergistic interaction between raised K+o and lowered muscle glycogen as the latter shifts the peak tetanic force–resting EM relationship towards more negative resting EM due to lowered sarcolemmal excitability, which hence may contribute to muscle fatigue.
Key points
Diminished muscle glycogen levels and raised extracellular potassium concentrations (K+o) occur simultaneously during intense exercise and together may contribute to muscle fatigue.
Prolonged exposure of isolated non‐fatigued soleus muscles of mice to glucose‐free physiological saline solutions markedly lowered muscle glycogen levels, as does fatigue then recovery in glucose‐free solutions. For both approaches, the subsequent decline of maximal force at 11 mM K+o, which mimics interstitial K+ levels during intense exercise, was exacerbated at lowered compared with normal glycogen. This was mainly due to many more muscle fibres becoming inexcitable.
We established an important relationship that provides evidence of a synergistic interaction between raised K+o and lowered glycogen content to reduce force production.
This paper indicates that partially lowered muscle glycogen (and/or metabolic stress) together with elevated interstitial K+ interactively lowers muscle force, and hence may diminish performance especially during repeated high‐intensity exercise.
figure legend The potassium–glycogen interaction is a potential mechanism of fatigue in exercise scenarios when glycogen is lowered and potassium (K+) disturbances occur, such as with repeated high‐intensity exercise. A prolonged glucose‐free condition lowers muscle glycogen, and then raised extracellular K+ (K+o) causes an exacerbated peak tetanic force depression in isolated mouse soleus muscles. This interaction involves many more fibres becoming inexcitable without added sarcolemmal depolarisation. Consequently, the peak tetanic force–resting membrane potential (EM) relationship is shifted towards more negative resting EM. Severe glycogen depletion is associated with increased phosphorylated 5′‐AMP‐activated protein kinase (AMPK), suggesting metabolic stress and possibly decreased ATP, which we speculate causes inexcitability by activating KATP and/or ClC‐1 channels. Increased K+ and chloride (Cl−) conductances (i.e. GK and GCl, respectively) likely increase subthreshold inhibitory currents to render some fibres inexcitable. There may also be reduced Na+–K+‐pump activity with lowered glycogen, although the present study does not support this notion.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that ...patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulate
gene transcription and increase VEGFC mRNA half-life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element-binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure.
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Background and objective
Case reports have suggested that continuous positive airway pressure (CPAP) telemonitoring can detect the onset of acute cardiac events such as decompensated heart failure ...(HF) or atrial fibrillation through an increase in the apnoea–hypopnoea index (AHI) and onset of Cheyne–Stokes Respiration (CSR). This study addressed whether long‐term remote CPAP treatment telemonitoring revealing CSR can help detect serious cardiac events (SCEs) in obstructive sleep apnoea (OSA) patients.
Methods
This monocentric prospective cohort study included adults receiving CPAP therapy for OSA with daily telemonitoring. Any sudden increase in AHI generated an alert for the home healthcare provider to download CPAP data to identify CSR. A medical consultation was scheduled if CSR was detected.
Results
We included 555 adults (412 men; 57% with known cardiovascular comorbidities). During the 1‐year follow‐up, 78 CSR episodes were detected in 74 patients (CSR+). The main conditions associated with incident CSR were HF (24 patients 30.8%), ventilatory instability (21, 26.9%), leaks (13, 16.7%), medications inducing central apnoeas (baclofen, ticagrelor, opioids) (7, 9.0%), arrhythmias (6, 7.7%) and renal failure (2, 2.6%). Fifteen (20.3%) CSR+ patients had a confirmed SCE. In univariable analysis, a CSR episode increased the risk of an SCE by 13.8‐fold (5.7–35.6) (p < 0.0001), with an adjusted OR of 5.7 (2.0–16.8) in multivariable analysis.
Conclusion
Long‐term telemonitoring of patients on CPAP treatment can alert CSR episodes and allows early detection of SCEs in patients with or without known cardiac comorbidities.
This study shows that telemonitoring data from continuous positive airway pressure devices, in particular sudden changes in the apnoea–hypopnoea index, is useful as a sensitive easily accessible indicator to alert for incident Cheyne–Stokes respiration, which is strongly associated with the onset of severe cardiac events such as heart failure or atrial fibrillation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle ...satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions. Inhibiting EGFR causes a substantial shift from asymmetric to symmetric division modes, whereas EGF treatment increases asymmetric divisions. EGFR activation acts through Aurka to orient mitotic centrosomes, and inhibiting Aurka blocks EGF stimulation-induced asymmetric division. In vivo EGF treatment markedly activates asymmetric divisions of dystrophin-deficient satellite cells in mdx mice, increasing progenitor numbers, enhancing regeneration, and restoring muscle strength. Therefore, activating an EGFR-dependent polarity pathway promotes functional rescue of dystrophin-deficient satellite cells and enhances muscle force generation.
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•EGFR expression and activation are polarized in satellite cells•EGF stimulates asymmetric satellite stem cell division•Polarized EGFR activation orients mitotic centrosomes through Aurka•EGF stimulation rescues mdx satellite cell function in vitro and in vivo
Wang et al. found that EGFR-Aurka signaling in muscle stem cells acts to direct apicobasally oriented mitoses and asymmetric cell division. EGF treatment rescues the reduction of asymmetric divisions in dystrophin-deficient satellite cells in mdx mice, resulting in increased numbers of progenitors and enhanced regeneration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Aims
Endoscopy is effective in management of bariatric surgery (BS) adverse events (AEs) but a comprehensive evaluation of long-term results is lacking. Our aim is to assess the ...effectiveness of a standardized algorithm for the treatment of BS-AE.
Patients and Methods
We retrospectively analyzed 1020 consecutive patients treated in our center from 2012 to 2020, collecting data on demographics, type of BS, complications, and endoscopic treatment. Clinical success (CS) was evaluated considering referral delay, healing time, surgery, and complications type. Logistic regression was performed to identify variables of CS.
Results
In the study period, we treated 339 fistulae (33.2%), 324 leaks (31.8%), 198 post-sleeve gastrectomy twist/stenosis (19.4%), 95 post-RYGB stenosis (9.3 %), 37 collections (3.6%), 15 LAGB migrations (1.5%), 7 weight regains (0.7%), and 2 hemorrhages (0.2%). Main endoscopic treatments were as follows: pigtail-stent positioning under endoscopic view for both leaks (CS 86.1%) and fistulas (CS 77.2%), or under EUS-guidance for collections (CS 88.2%); dilations and/or stent positioning for sleeve twist/stenosis (CS 80.6%) and bypass stenosis (CS 81.5%). After a median (IQR) follow-up of 18.5 months (4.29–38.68), complications rate was 1.9%. We found a 1% increased risk of redo-surgery every 10 days of delay to the first endoscopic treatment. Endoscopically treated patients had a more frequent regular diet compared to re-operated patients.
Conclusions
Endoscopic treatment of BS-AEs following a standardized algorithm is safe and effective. Early endoscopic treatment is associated with an increased CS rate.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of ...utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.
Wnt7a treatment ameliorates muscular dystrophy von Maltzahn, Julia; Renaud, Jean-Marc; Parise, Gianni ...
Proceedings of the National Academy of Sciences - PNAS,
12/2012, Volume:
109, Issue:
50
Journal Article
Peer reviewed
Open access
Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder of childhood marked by progressive debilitating muscle weakness and wasting, and ultimately death in the second or third ...decade of life. Wnt7a signaling through its receptor Fzd7 accelerates and augments regeneration by stimulating satellite stem cell expansion through the planar cell polarity pathway, as well as myofiber hypertrophy through the AKT/mammalian target of rapamycin (mTOR) anabolic pathway. We investigated the therapeutic potential of the secreted factor Wnt7a for focal treatment of dystrophic DMD muscles using the mdx mouse model, and found that Wnt7a treatment efficiently induced satellite cell expansion and myofiber hypertrophy in treated mucles in mdx mice. Importantly, Wnt7a treatment resulted in a significant increase in muscle strength, as determined by generation of specific force. Furthermore, Wnt7a reduced the level of contractile damage, likely by inducing a shift in fiber type toward slow-twitch. Finally, we found that Wnt7a similarly induced myotube hypertrophy and a shift in fiber type toward slow-twitch in human primary myotubes. Taken together, our findings suggest that Wnt7a is a promising candidate for development as an ameliorative treatment for DMD.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Flash Sintering (FS), that allows densifying ceramics at low furnace temperature in a few seconds, requires a reversible electrochemical reaction to enable the current flow through the electrode / ...material interface. For Li+ pure ionic conductors such as Li1.3Al0.3Ti1.7(PO4)3 (LATP), the best material to ensure this fast charge transfer reaction is a mixed Li+/e− conductor, eg, LiCoO2 (LCO). This paper demonstrates the feasibility of FS on LCO between two Pt electrodes and on multi‐layers systems using LCO or LATP+LCO composite as electrodes. It is shown that a composite electrode both allows the flash event to occur and prevents the delamination possibly observed with pure LCO by lowering interfacial stresses.
Flash sintering of cationic ceramics: need for a reversible electrochemical reaction.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
One of the most important but less understood step of epithelial tumourigenesis occurs when cells acquire the ability to leave their epithelial compartment. This phenomenon, described as basal ...epithelial cell extrusion (basal extrusion), represents the first step of tumour invasion. However, due to lack of adequate in vivo model, implication of emblematic signalling pathways such as Ras/Mitogen-Activated Protein Kinase (MAPK) and phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathways, is scarcely described in this phenomenon. We have developed a unique model of basal extrusion in the Drosophila accessory gland. There, we demonstrate that both Ras/MAPK and PI3K/AKT/mTOR pathways are necessary for basal extrusion. Furthermore, as in prostate cancer, we show that these pathways are co-activated. This occurs through set up of Epidermal Growth Factor Receptor (EGFR) and Insulin Receptor (InR) dependent autocrine loops, a phenomenon that, considering human data, could be relevant for prostate cancer.
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