Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and ...extended rehabilitation. This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of the α-motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates. Loss of muscle mass with aging, which is largely due to the progressive loss of motoneurons, is associated with reduced muscle fiber number and size. Muscle function progressively declines because motoneuron loss is not adequately compensated by reinnervation of muscle fibers by the remaining motoneurons. At the intracellular level, key factors are qualitative changes in posttranslational modifications of muscle proteins and the loss of coordinated control between contractile, mitochondrial, and sarcoplasmic reticulum protein expression. Quantitative and qualitative changes in skeletal muscle during the process of aging also have been implicated in the pathogenesis of acquired and hereditary neuromuscular disorders. In experimental models, specific intervention strategies have shown encouraging results on limiting deterioration of motor unit structure and function under conditions of impaired innervation. Translated to the clinic, if these or similar interventions, by saving muscle and improving mobility, could help alleviate sarcopenia in the elderly, there would be both great humanitarian benefits and large cost savings for health care systems.
Gut microbiota is involved in the development of several chronic diseases, including diabetes, obesity, and cancer, through its interactions with the host organs. It has been suggested that the cross ...talk between gut microbiota and skeletal muscle plays a role in different pathological conditions, such as intestinal chronic inflammation and cachexia. However, it remains unclear whether gut microbiota directly influences skeletal muscle function. In this work, we studied the impact of gut microbiota modulation on mice skeletal muscle function and investigated the underlying mechanisms. We determined the consequences of gut microbiota depletion after treatment with a mixture of a broad spectrum of antibiotics for 21 days and after 10 days of natural reseeding. We found that, in gut microbiota-depleted mice, running endurance was decreased, as well as the extensor digitorum longus muscle fatigue index in an ex vivo contractile test. Importantly, the muscle endurance capacity was efficiently normalized by natural reseeding. These endurance changes were not related to variation in muscle mass, fiber typology, or mitochondrial function. However, several pertinent glucose metabolism markers, such as ileum gene expression of short fatty acid chain and glucose transporters G protein-coupled receptor 41 and sodium-glucose cotransporter 1 and muscle glycogen level, paralleled the muscle endurance changes observed after treatment with antibiotics for 21 days and reseeding. Because glycogen is a key energetic substrate for prolonged exercise, modulating its muscle availability via gut microbiota represents one potent mechanism that can contribute to the gut microbiota-skeletal muscle axis. Taken together, our results strongly support the hypothesis that gut bacteria are required for host optimal skeletal muscle function.
Emerging evidence suggests that the T helper 17 (T(H)17) subset of αβ T cells contributes to the development of allergic asthma. In this study, we found that mice lacking the αvβ8 integrin on ...dendritic cells did not generate T(H)17 cells in the lung and were protected from airway hyper-responsiveness in response to house dust mite and ovalbumin sensitization and challenge. Because loss of T(H)17 cells inhibited airway narrowing without any obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of T(H)17 cytokines on mouse and human airway smooth muscle function. Interleukin-17A (IL-17A), but not IL-17F or IL-22, enhanced contractile force generation of airway smooth muscle through an IL-17 receptor A (IL-17RA)-IL-17RC, nuclear factor κ light-chain enhancer of activated B cells (NF-κB)-ras homolog gene family, member A (RhoA)-Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after ovalbumin sensitization and challenge, and the diminished contraction of the tracheal rings in these mice was reversed by IL-17A. These data indicate that the IL-17A produced by T(H)17 cells contributes to allergen-induced airway hyper-responsiveness through direct effects on airway smooth muscle.
Pelvic floor muscle training (PFMT) is the most commonly used physical therapy treatment for women with stress urinary incontinence (SUI). It is sometimes also recommended for mixed urinary ...incontinence (MUI) and, less commonly, urgency urinary incontinence (UUI).This is an update of a Cochrane Review first published in 2001 and last updated in 2014.
To assess the effects of PFMT for women with urinary incontinence (UI) in comparison to no treatment, placebo or sham treatments, or other inactive control treatments; and summarise the findings of relevant economic evaluations.
We searched the Cochrane Incontinence Specialised Register (searched 12 February 2018), which contains trials identified from CENTRAL, MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, WHO ICTRP, handsearching of journals and conference proceedings, and the reference lists of relevant articles.
Randomised or quasi-randomised controlled trials in women with SUI, UUI or MUI (based on symptoms, signs or urodynamics). One arm of the trial included PFMT. Another arm was a no treatment, placebo, sham or other inactive control treatment arm.
At least two review authors independently assessed trials for eligibility and risk of bias. We extracted and cross-checked data. A third review author resolved disagreements. We processed data as described in the Cochrane Handbook for Systematic Reviews of Interventions. We subgrouped trials by diagnosis of UI. We undertook formal meta-analysis when appropriate.
The review included 31 trials (10 of which were new for this update) involving 1817 women from 14 countries. Overall, trials were of small-to-moderate size, with follow-ups generally less than 12 months and many were at moderate risk of bias. There was considerable variation in the intervention's content and duration, study populations and outcome measures. There was only one study of women with MUI and only one study with UUI alone, with no data on cure, cure or improvement, or number of episodes of UI for these subgroups.Symptomatic cure of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were eight times more likely to report cure (56% versus 6%; risk ratio (RR) 8.38, 95% confidence interval (CI) 3.68 to 19.07; 4 trials, 165 women; high-quality evidence). For women with any type of UI, PFMT groups were five times more likely to report cure (35% versus 6%; RR 5.34, 95% CI 2.78 to 10.26; 3 trials, 290 women; moderate-quality evidence).Symptomatic cure or improvement of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were six times more likely to report cure or improvement (74% versus 11%; RR 6.33, 95% CI 3.88 to 10.33; 3 trials, 242 women; moderate-quality evidence). For women with any type of UI, PFMT groups were two times more likely to report cure or improvement than women in the control groups (67% versus 29%; RR 2.39, 95% CI 1.64 to 3.47; 2 trials, 166 women; moderate-quality evidence).UI-specific symptoms and quality of life (QoL) at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT group were more likely to report significant improvement in UI symptoms (7 trials, 376 women; moderate-quality evidence), and to report significant improvement in UI QoL (6 trials, 348 women; low-quality evidence). For any type of UI, women in the PFMT group were more likely to report significant improvement in UI symptoms (1 trial, 121 women; moderate-quality evidence) and to report significant improvement in UI QoL (4 trials, 258 women; moderate-quality evidence). Finally, for women with mixed UI treated with PFMT, there was one small trial (12 women) reporting better QoL.Leakage episodes in 24 hours at the end of treatment: PFMT reduced leakage episodes by one in women with SUI (mean difference (MD) 1.23 lower, 95% CI 1.78 lower to 0.68 lower; 7 trials, 432 women; moderate-quality evidence) and in women with all types of UI (MD 1.00 lower, 95% CI 1.37 lower to 0.64 lower; 4 trials, 349 women; moderate-quality evidence).Leakage on short clinic-based pad tests at the end of treatment: women with SUI in the PFMT groups lost significantly less urine in short (up to one hour) pad tests. The comparison showed considerable heterogeneity but the findings still favoured PFMT when using a random-effects model (MD 9.71 g lower, 95% CI 18.92 lower to 0.50 lower; 4 trials, 185 women; moderate-quality evidence). For women with all types of UI, PFMT groups also reported less urine loss on short pad tests than controls (MD 3.72 g lower, 95% CI 5.46 lower to 1.98 lower; 2 trials, 146 women; moderate-quality evidence).Women in the PFMT group were also more satisfied with treatment and their sexual outcomes were better. Adverse events were rare and, in the two trials that did report any, they were minor. The findings of the review were largely supported by the 'Summary of findings' tables, but most of the evidence was downgraded to moderate on methodological grounds. The exception was 'participant-perceived cure' in women with SUI, which was rated as high quality.
Based on the data available, we can be confident that PFMT can cure or improve symptoms of SUI and all other types of UI. It may reduce the number of leakage episodes, the quantity of leakage on the short pad tests in the clinic and symptoms on UI-specific symptom questionnaires. The authors of the one economic evaluation identified for the Brief Economic Commentary reported that the cost-effectiveness of PFMT looks promising. The findings of the review suggest that PFMT could be included in first-line conservative management programmes for women with UI. The long-term effectiveness and cost-effectiveness of PFMT needs to be further researched.
The steady-state isometric force after active shortening of a skeletal muscle is lower than the purely isometric force at the corresponding length. This property of skeletal muscle is known as force ...depression. The purpose of this study was to investigate whether the energy cost of force production at the steady state after active shortening was reduced compared with the energy cost of force production for a purely isometric contraction performed at the corresponding length (same length, same activation). Experiments were performed in skinned fibres isolated from rabbit psoas muscle. Skinned fibres were actively shortened from an average sarcomere length of 3.0 µm to an average sarcomere length of 2.4 µm. Purely isometric reference contractions were performed at an average sarcomere length of 2.4 µm. Simultaneously with the force measurements, the ATP cost was measured during the last 30 s of isometric contractions using an enzyme-coupled assay. Stiffness was calculated during a quick stretch-release cycle of 0.2% fibre length performed once the steady state had been reached after active shortening and during the purely isometric reference contractions. Force and stiffness following active shortening were decreased by 10.0±1.8% and 11.0±2.2%, respectively, compared with the isometric reference contractions. Similarly, ATPase activity per second (not normalized to the force) showed a decrease of 15.6±3.0% in the force-depressed state compared with the purely isometric reference state. However, ATPase activity per second per unit of force was similar for the isometric contractions following active shortening (28.7±2.4 mmol l
mN
s mm
) and the corresponding purely isometric reference contraction (30.9±2.8 mmol l
mN
s mm
). Furthermore, the reduction in absolute ATPase activity per second was significantly correlated with force depression and stiffness depression. These results are in accordance with the idea that force depression following active shortening is primarily caused by a decrease in the proportion of attached cross-bridges. Furthermore, these findings, along with previously reported results showing a decrease in ATP consumption per unit of force after active muscle stretching, suggest that the mechanisms involved in the steady-state force after active muscle shortening and active muscle lengthening are of distinctly different origin.
Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. We recently demonstrated that AMPK is necessary for AICAR, contraction, and ...exercise to enhance muscle and whole-body insulin sensitivity in mice. Correlative observations from both human and rodent skeletal muscle suggest that regulation of the phosphorylation status of TBC1D4 may relay this insulin sensitization. However, the necessity of TBC1D4 for this phenomenon has not been proven. Thus, the purpose of this study was to determine whether TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction. We found that immediately after contraction and AICAR stimulation, phosphorylation of AMPKα-Thr172 and downstream targets were increased similarly in glycolytic skeletal muscle from wild-type and TBC1D4-deficient mice. In contrast, 3 h after contraction or 6 h after AICAR stimulation, enhanced insulin-stimulated glucose uptake was evident in muscle from wild-type mice only. The enhanced insulin sensitivity in muscle from wild-type mice was associated with improved insulin-stimulated phosphorylation of TBC1D4 (Thr649 and Ser711) but not of TBC1D1. These results provide genetic evidence linking signaling through TBC1D4 to enhanced muscle insulin sensitivity after activation of the cellular energy sensor AMPK.
A combination of extrinsic (passive) and intrinsic (active) forces move lymph against a hydrostatic pressure gradient in most regions of the body. The effectiveness of the lymph pump system impacts ...not only interstitial fluid balance but other aspects of overall homeostasis. This review focuses on the mechanisms that regulate the intrinsic, active contractions of collecting lymphatic vessels in relation to their ability to actively transport lymph. Lymph propulsion requires not only robust contractions of lymphatic muscle cells, but contraction waves that are synchronized over the length of a lymphangion as well as properly functioning intraluminal valves. Normal lymphatic pump function is determined by the intrinsic properties of lymphatic muscle and the regulation of pumping by lymphatic preload, afterload, spontaneous contraction rate, contractility and neural influences. Lymphatic contractile dysfunction, barrier dysfunction and valve defects are common themes among pathologies that directly involve the lymphatic system, such as inherited and acquired forms of lymphoedema, and pathologies that indirectly involve the lymphatic system, such as inflammation, obesity and metabolic syndrome, and inflammatory bowel disease.
Diagram depicting the major factors regulating the effective pumping ability of a prenodal collecting lymphatic vessel as it transports lymph formed in lymphatic capillaries to the subcapsular sinus of a lymph node. Pressures indicate approximate hydrostatic pressures measured in the interstitium and at the entrance to the lymph node, respectively, that have been recorded in many regions of the lymphatic system. Cut‐away sections show the locations of two valves. The blue shaded region depicts the relatively modest net filtration of fluid and solute that occurs under normal conditions all along the length of the collecting vessel. Each of these factors can also become a target of lymphatic dysfunction. AP, action potential; LEC, lymphatic endothelial cell; LMC, lymphatic muscle cell.
An eccentric contraction involves the active lengthening of muscle under an external load. The molecular and neural mechanisms underpinning eccentric contractions differ from those of concentric and ...isometric contractions and remain less understood. A number of molecular theories have been put forth to explain the unexplained observations during eccentric contractions that deviate from the predictions of the established theories of muscle contraction. Postulated mechanisms include a strain-induced modulation of actin-myosin interactions at the level of the cross-bridge, the activation of the structural protein titin, and the winding of titin on actin. Accordingly, neural strategies controlling eccentric contractions also differ with a greater, and possibly distinct, cortical activation observed despite an apparently lower activation at the level of the motor unit. The characteristics of eccentric contractions are associated with several acute physiological responses to eccentrically-emphasised exercise. Differences in neuromuscular, metabolic, hormonal and anabolic signalling responses during, and following, an eccentric exercise bout have frequently been observed in comparison to concentric exercise. Subsequently, the high levels of muscular strain with such exercise can induce muscle damage which is rarely observed with other contraction types. The net result of these eccentric contraction characteristics and responses appears to be a novel adaptive signal within the neuromuscular system.
Abstract A noninvasive, immediate, and convenient method for assessing muscle tissue status during exercise-induced muscle damage (EIMD) has not been established. This study was designed to assess ...and determine parameters suitable for measuring EIMD after eccentric exercise, using multi-frequency bioimpedance analysis (BIA). Thirty-five young male participants performed dumbbell exercises with their left arm, and their BIA parameters were measured at various time points up to 168 h post exercise using a multi-frequency BIA device. At all-time points, intra and extracellular water content was greater in the left arm than in the right arm, whereas the impedance, reactance, resistance, and phase angle were lower in the left arm than in the right arm. Established EIMD indices, such as maximal isometric voluntary contraction, were measured and used in correlational analyses. Only reactance was correlated with biomarkers, indicating muscle damage (r = − 0.56 to − 0.49). Furthermore, reactance was found to correlate well with indirect indicators of EIMD, suggesting that it may be a suitable marker for evaluating EIMD. However, the relationship with the limited evaluation indices employed in this study is constrained. Future studies should investigate the correlation between reactance and direct damage indicators, such as structural damage, observed in biopsies.
Histone deacetylases (HDACs) are a family of enzymes that mediate nucleosomal histone deacetylation and gene expression. Some members of the HDAC family have also been implicated in nonhistone ...protein deacetylation, which modulates cell-cycle control, differentiation, and cell migration. However, the role of HDACs in smooth muscle contraction is largely unknown. Here, HDAC8 was localized both in the cytoplasm and the nucleus of mouse and human smooth muscle cells. Knockdown of HDAC8 by lentivirus-encoding HDAC8 shRNA inhibited force development in response to acetylcholine. Treatment of smooth muscle tissues with HDAC8 inhibitor XXIV (OSU-HDAC-44) induced relaxation of precontracted smooth muscle tissues. In addition, cortactin is an actin-regulatory protein that undergoes deacetylation during migration of NIH 3T3 cells. In this study, acetylcholine stimulation induced cortactin deacetylation in mouse and human smooth muscle tissues, as evidenced by immunoblot analysis using antibody against acetylated lysine. Knockdown of HDAC8 by RNAi or treatment with the inhibitor attenuated cortactin deacetylation and actin polymerization without affecting myosin activation. Furthermore, expression of a charge-neutralizing cortactin mutant inhibited contraction and actin dynamics during contractile activation. These results suggest a novel mechanism for the regulation of smooth muscle contraction. In response to contractile stimulation, HDAC8 may mediate cortactin deacetylation, which subsequently promotes actin filament polymerization and smooth muscle contraction.
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