Blood lactate increases during incremental exercise at high-intensity workloads, and limited exercise capacity is a characteristic of obese animals. This study examined whether blood lactate changes in response to incremental exercise is disrupted in obese animals. Muscular and hepatic proteins that are critical in lactate metabolism were also investigated. Rats were randomized to either standard chow (control) or high-fat diet (HFD) groups. All animals underwent an incremental treadmill test after 14 wk of diet intervention. Blood lactate levels were measured before and after the treadmill test. Activities of mitochondrial oxidative phosphorylation and glycolysis were examined in muscle tissues. Proteins in the liver and skeletal muscles that participate in the turnover of blood lactate were determined by Western blot. Running time in the incremental treadmill test decreased in the HFD group, and blood lactate accumulated faster in these animals than in the control group. Animals with HFD had a decreased level of hepatic monocarboxylate transporter 2, the protein responsible for blood lactate uptake in the liver. Skeletal muscles of animals with HFD showed greater glycolytic activity and decreased content of lactate dehydrogenase B, which converts lactate to pyruvate. We conclude that blood lactate accumulated faster during incremental exercise in obese animals and was associated with their decreased exercise performance. Changes in the metabolic pattern of muscles and changes of liver and muscle proteins associated with lactate utilization likely contribute to the abnormal response of blood lactate to incremental exercise in obese animals.
Background: Skeletal muscle injuries are very common in sports medicine. Conventional therapies have limited clinical efficacy. New treatment methods should be developed to allow athletes to return to play with better function. Purpose: To evaluate the in vitro differentiation potential of bone marrow–derived mesenchymal stem cells and the in vivo histologic and physiologic effects of mesenchymal stem cell therapy on muscle healing after contusion injury. Study Design: Controlled laboratory study. Methods: Bone marrow cells were flushed from both femurs of 5-week-old C57BL/6 mice to establish immortalized mesenchymal stem cell lines. A total of 36 mice aged 8 to 10 weeks were used to develop a muscle contusion model and were divided into 6 groups (6 mice/group) on the basis of the different dosages of IM2 cells to be injected (0, 1.25 × 10 5 , and 2.5 × 10 5 cells with/without F-127 in 100 μL of phosphate-buffered saline). Histological analysis of muscle regeneration was performed, and the fast-twitch and tetanus strength of the muscle contractions was measured 28 days after muscle contusion injury, after injections of different doses of mesenchymal stem cells with or without the F-127 scaffold beginning 14 days after contusion injury. Results: The mesenchymal stem cell–treated muscles exhibited numerous regenerating myofibers. All the groups treated with mesenchymal stem cells (1.25 × 10 5 cells, 2.5 × 10 5 cells, 1.25 × 10 5 cells plus F-127, and 2.5 × 10 5 cells plus F-127) exhibited a significantly higher number of regenerating myofibers (mean ± SD: 111.6 ± 14.77, 133.4 ± 21.44, 221.89 ± 32.65, and 241.5 ± 25.95, respectively) as compared with the control group and the control with F-127 (69 ± 18.79 and 63.2 ± 18.98). The physiologic evaluation of fast-twitch and tetanus strength did not reveal differences between the age-matched uninjured group and the groups treated with various doses of mesenchymal stem cells 28 days after contusion. Significant differences were found between the control group and the groups treated with various doses of mesenchymal stem cells after muscle contusion. Conclusion: Mesenchymal stem cell therapy increased the number of regenerating myofibers and improved fast-twitch and tetanus muscle strength in a mouse model of muscle contusion. However, the rapid decay of transplanted mesenchymal stem cells suggests a paracrine effect of this action. Treatment with mesenchymal stem cells at various doses combined with the F-127 scaffold is a potential therapy for a muscle contusion. Clinical Relevance: Mesenchymal stem cell therapy has an effect on sports medicine because of its effects on myofiber regeneration and muscle strength after contusion injury.
Abstract Objective Emerging evidence has documented the beneficial effects of sodium glucose cotransporter 2 (SGLT2) inhibitors on reducing cardiovascular events. Beyond glucose regulation, the mechanisms behind their cardioprotective effects still remained unresolved. This study aims to investigate whether these benefits are mediated by their effects on vascular smooth muscle cell (VSMC) functions. Approach and Results Treatment of non-diabetic rats with empagliflozin (a SGLT2 inhibitor) attenuated balloon injury-induced neointimal formation in carotid arteries. In vitro , treatment of rat VSMCs with empagliflozin reduced platelet-derived growth factor (PDGF)-BB-induced proliferation and migration. Moreover, empagliflozin-treated VSMCs did not undergo apoptosis and cytosis. Notably, treating VSMCs with empagliflozinsuppressed the activation of PDGF-related signaling, such as that related to the phosphorylation of PDGF receptor b (PDGF-Rb), Akt, and STAT3. Furthermore, overactivation of PDGF-related signaling attenuated the inhibitory effects of empagliflozin on VSMC proliferation and migration. The relevant in vitro findings were corroborated in the neointima of empagliflozin-treated rats. The fact that minimal SGLT2 was discovered in rat VSMCs and SGLT2 silencing did not alter the effect of empagliflozin supported the SGLT2-independent effect of empagliflozin on VSMC functions. Conclusions This study highlights the crucial role of PDGF-related signaling in mediating the beneficial effects of empagliflozin on VSMC functions and/or neointimal formation, which are independent of its effects on SGLT2 and glucose metabolism.
Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator-induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high-mobility group box-1 (HMGB1) levels are associated with patients requiring long-term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti-HMGB1 antibody could attenuate sepsis-exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti-HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor-1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia (P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti-HMGB1 antibody (P < 0.05). Our data suggest that EP attenuates endotoxin-enhanced VIDD by inhibiting HMGB1 signalling pathway.
There is an urgency to develop robust prognostic biomarkers for metastatic colorectal cancer (mCRC) patients receiving chemotherapy. The current study aimed to examine the prognostic significance of circulating tumour cells (CTCs) and to develop a prognostic model incorporating CTCs in predicting the outcomes of mCRC patients treated with chemotherapy.
The pharmacological activities of liriodenine, isolated from Fissistigma glaucescens , were determined in isolated trachea, ileum and cardiac tissues of guinea‐pigs. Liriodenine was found to be a muscarinic receptor antagonist in guinea‐pig trachea as revealed by its competitive antagonism of carbachol (pA 2 = 6.22 ± 0.08)‐induced smooth muscle contraction. It was slightly more potent than methoctramine (pA 2 = 5.92 ± 0.05), but was less potent than atropine (pA 2 = 8.93 ± 0.07), pirenzepine (pA 2 = 7.02 ± 0.09) and 4‐diphenylacetoxy‐ N ‐methylpiperidine (4‐DAMP, pA 2 = 8.72 ± 0.07). Liriodenine was also a muscarinic antagonist in guinea‐pig ileum (pA 2 = 6.36 ± 0.10) with a pA 2 value that closely resembled that obtained in the trachea. Liriodenine was 10 fold less potent in atrial preparations (left atria, pA 2 = 5.24 ± 0.04; right atria, pA 2 = 5.35 ± 0.09 and 5.28 ± 0.07 for inotropic and chronotropic effects, respectively) than in smooth muscle preparations. High concentration of liriodenine (300 μ m ) partially depressed the contractions induced by U‐46619, histamine, prostaglandin F 2a , neurokinin A, leukotriene C 4 and high K + in the guinea‐pig trachea. The inhibitions were characterized by a rightward shift in the concentration‐response curves with suppression of their maximal contraction. High concentration of liriodenine (300 μ m ) did not affect U‐46619‐ or neurokinin A‐induced tracheal contraction in the presence of nifedipine (1 μ m ) or in Ca 2+ ‐free (containing 0.2 m m EGTA) medium. Neither cyclic AMP nor cyclic GMP content of guinea‐pig trachealis was changed by liriodenine (30–300 μ m ). 8 It is concluded that liriodenine is a selective muscarinic receptor antagonist in isolated trachea, ileum and cardiac tissues of guinea‐pigs. It is more potent in smooth muscle than in cardiac preparations. It also acts as a blocker of voltage‐dependent Ca 2+ channels at a high concentration (300 μ m ).
This study was designed to examine the antiarrhythmic efficacy and the underlying mechanisms of the benzyl-furoquinoline vasodilator, CIJ-3-2F, in rat cardiac preparations.Conduction electrograms and left ventricular pressure were determined in Langendorff-perfused hearts. Action potentials were assessed with microelectrode techniques, calcium transients by fura-2 fluorescence and ionic currents by whole-cell patch-clamp techniques.In isolated hearts, CIJ-3-2F prolonged sinus cycle length, QT interval, Wenckebach cycle length, atrio-His bundle and His bundle-ventricular conduction intervals, refractory periods in atrium, AV node, His-Purkinje system and ventricle, and also increased left ventricular pressure. CIJ-3-2F reduced the incidences of both ischaemic and reperfusion-induced ventricular arrhythmias and prevented the induction of atrial tachyarrhythmias. In both atrial and papillary muscles, CIJ-3-2F decreased upstroke velocity and prolonged duration of the action potential. In ventricular myocytes, CIJ-3-2F moderately increased the amplitude of [Ca(2+)]i transients and cell shortening. CIJ-3-2F inhibited the transient outward K(+) current (Ito ) (IC₅₀ = 4.4 μM) with accelerated inactivation, a slower rate of recovery from inactivation and use-dependency. CIJ-3-2F also suppressed the steady-state outward K(+) current (Iss , IC₅₀ = 3.6 μM, maximum inhibition = 65.7%) and both the inward Na(+) current (INa , IC₅₀ = 2.8 μM) and L-type Ca(2+) current (ICa,L , IC₅₀ = 4.9 μM, maximum inhibition = 69.4%).CIJ-3-2F blocked Na(+) and Ito channels and, to some extent, also blocked Ca(2+) and Iss channels, modifying cardiac electromechanical function. These effects are likely to underlie its antiarrhythmic properties.
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