Aging of human skeletal muscles is associated with increased passive stiffness, but it is still debated whether muscle fibers or extracellular matrix (ECM) are the determinants of such change. To ...answer this question, we compared the passive stress generated by elongation of fibers alone and arranged in small bundles in young healthy (Y: 21 years) and elderly (E: 67 years) subjects. The physiological range of sarcomere length (SL) 2.5-3.3 μm was explored. The area of ECM between muscle fibers was determined on transversal sections with picrosirius red, a staining specific for collagen fibers. The passive tension of fiber bundles was significantly higher in E compared to Y at all SL. However, the resistance to elongation of fibers alone was not different between the two groups, while the ECM contribution was significantly increased in E compared to Y. The proportion of muscle area occupied by ECM increased from 3.3% in Y to 8.2% in E. When the contribution of ECM to bundle tension was normalized to the fraction of area occupied by ECM, the difference disappeared. We conclude that, in human skeletal muscles, the age-related reduced compliance is due to an increased stiffness of ECM, mainly caused by collagen accumulation.
In the present study, we found that CBD inhibited U87-MG and T98G cell proliferation and invasiveness in vitro and caused a decrease in the expression of a set of proteins specifically involved in ...growth, invasion and angiogenesis. In addition, CBD treatment caused a dose-related down-regulation of ERK and Akt prosurvival signaling pathways in U87-MG and T98G cells and decreased hypoxia inducible factor HIF-1α expression in U87-MG cells. Taken together, these results provide new insights into the antitumor action of CBD, showing that this cannabinoid affects multiple tumoral features and molecular pathways. As CBD is a non-psychoactive phytocannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anti-cancer drug in the management of gliomas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Experimental evidence implicates reactive oxygen species (ROS) generation in the hypoxic stabilization of hypoxia-inducible factor (HIF)-1α and in the subsequent expression of promoters of tumor ...invasiveness and metastatic spread. However, the role played by mitochondrial ROS in hypoxia-induced Epithelial-Mesenchymal Transition (EMT) activation is still unclear. This study was aimed at testing the hypothesis that the inhibition of hypoxia-induced mitochondrial ROS production, mainly at the mitochondrial Complex III UQCRB site, could result in the reversion of EMT, in addition to decreased HIF-1α stabilization. The role of hypoxia-induced ROS increase in HIF-1α stabilization and the ability of antioxidants, some of which directly targeting mitochondrial Complex III, to block ROS production and HIF-1α stabilization and prevent changes in EMT markers were assessed by evaluating ROS, HIF-1α and EMT markers on breast cancer cells, following 48 h treatment with the antioxidants. The specific role of UQCRB in hypoxia-induced EMT was also evaluated by silencing its expression through RNA interference and by assessing the effects of its downregulation on ROS production, HIF-1α levels, and EMT markers. Our results confirm the pivotal role of UQCRB in hypoxic signaling inducing EMT. Thus, UQCRB might be a new therapeutic target for the development of drugs able to reverse EMT by blocking mitochondrial ROS production.
Ageing is accompanied by an inexorable loss of muscle mass and functionality and represents a major risk factor for numerous diseases such as cancer, diabetes and cardiovascular and pulmonary ...diseases. This progressive loss of muscle mass and function may also result in the insurgence of a clinical syndrome termed sarcopenia, exacerbated by inactivity and disease. Sarcopenia and muscle weakness yield the risk of falls and injuries, heavily impacting on health and social costs. Thus, screening, monitoring and prevention of conditions inducing muscle wasting and weakness are essential to improve life quality in the ageing modern society. To this aim, the reliability of easily accessible and non‐invasive blood‐derived biomarkers is being evaluated. C‐terminal agrin fragment (CAF) has been widely investigated as a neuromuscular junction (NMJ)‐related biomarker of muscle dysfunction. This narrative review summarizes and critically discusses, for the first time, the studies measuring CAF concentration in young and older, healthy and diseased individuals, cross‐sectionally and in response to inactivity and physical exercise, providing possible explanations behind the discrepancies observed in the literature. To identify the studies investigating CAF in the above‐mentioned conditions, all the publications found in PubMed, written in English and measuring this biomarker in blood from 2013 (when CAF was firstly measured in human serum) to 2022 were included in this review. CAF increases with age and in sarcopenic individuals when compared with age‐matched, non‐sarcopenic peers. In addition, CAF was found to be higher than controls in other muscle wasting conditions, such as diabetes, COPD, chronic heart failure and stroke, and in pancreatic and colorectal cancer cachectic patients. As agrin is also expressed in kidney glomeruli, chronic kidney disease and transplantation were shown to have a profound impact on CAF independently from muscle wasting. CAF concentration raises following inactivity and seems to be lowered or maintained by exercise training. Finally, CAF was reported to be cross‐sectionally correlated to appendicular lean mass, handgrip and gait speed; whether longitudinal changes in CAF are associated with those in muscle mass or performance following physical exercise is still controversial. CAF seems a reliable marker to assess muscle wasting in ageing and disease, also correlating with measurements of appendicular lean mass and muscle function. Future research should aim at enlarging sample size and accurately reporting the medical history of each patient, to normalize for any condition, including chronic kidney disease, that may influence the circulating concentration of this biomarker.
Background
The assessment of muscle mass is a key determinant of the diagnosis of sarcopenia. We introduce for the first time an ultrasound imaging method for diagnosing sarcopenia based on changes ...in muscle geometric proportions.
Methods
Vastus lateralis muscle fascicle length (Lf) and thickness (Tm) were measured at 35% distal femur length by ultrasonography in a population of 279 individuals classified as moderately active elderly (MAE), sedentary elderly (SE) (n = 109), mobility impaired elderly (MIE) (n = 43), and in adult young controls (YC) (n = 60). The ratio of Lf/Tm was calculated to obtain an ultrasound index of the loss of muscle mass associated with sarcopenia (USI). In a subsample of elderly male individuals (n = 76) in which corresponding DXA measurements were available (MAE, n = 52 and SE, n = 24), DXA‐derived skeletal muscle index (SMI, appendicular limb mass/height2) was compared with corresponding USI values.
Results
For both young and older participants, USI values were found to be independent of sex, height and body mass. USI values were 3.70 ± 0.52 for YC, 4.50 ± 0.72 for the MAE, 5.05 ± 1.11 for the SE and 6.31 ± 1.38 for the MIE, all significantly different between each other (P < 0.0001). Based on the USI Z‐scores, with reference to the YC population, the 219 elderly participants were stratified according to their muscle sarcopenic status. Individuals with USI values within a range of 3.70 < USI ≥ 4.23 were classified as non‐sarcopenic (prevalence 23.7%), those with USI values within 4.23 < USI ≥ 4.76 were classified as pre‐sarcopenic (prevalence 23.7%), those with USI values within 4.76 < USI ≥ 5.29 were classified as moderately sarcopenic (prevalence 15.1%), those with USI values within range 5.29 < USI ≥ 5.82 were classified as sarcopenic (prevalence 27.9%), and those with USI values >5.82 were classified as severely sarcopenic (prevalence 9.6%). The DXA‐derived SMI was found to be significantly correlated with USI (r = 0.61, P < 0.0001). Notably, the USI cut‐off value for moderate sarcopenia (4.76 a.u.) was found to coincide with the DXA cut‐off value of sarcopenia (7.26 kg/m2).
Conclusions
We propose a novel, practical, and inexpensive imaging marker of the loss of muscle mass associated with sarcopenia, called the ultrasound sarcopenic index (USI), based on changes in muscle geometric proportions. These changes provide a useful ‘signature of sarcopenia’ and allow the stratification of individuals according to the presence and severity of muscle sarcopenia. We are convinced that the USI will be a useful clinical tool for confirming the diagnosis of sarcopenia, of which the assessment of muscle mass is a key‐component.
An autocrine circuit, involving IGF1R, STAT3, HIF1α and IGF-II operates in human glioblastoma cells.
Inappropriate activation of the IGF (insulin-like growth factor) system has been implicated in the ...growth and progression of a number of tumor types. Recent evidence indicates a possible role for the IGF system in modulating/mediating tumor cell response to hypoxia, a common occurrence in solid tumors, and particularly in malignant gliomas, causing tumor cells either to die, or to mount a pleiotropic adaptive response that is mainly orchestrated through activation of the hypoxia-inducible transcription factor HIF1. Experimental evidence suggests possible links between IGF- and HIF1-dependent signaling pathways, as well as a role for activated STAT3 in mediating their activities. Interestingly,
igf2 is among the target genes transactivated by HIF1, thereby providing the missing link in a hypothetical autocrine self-amplifying circuit.
The present study investigates the presence of the IGF-HIF1-VEGF axis in the human glioma cell line U-87 MG, and characterizes its molecular effectors. Our results show that exogenous IGF-I causes IGF1R and STAT3 activation, and increases HIF1α protein levels and HIF1 trascriptional activity, inducing VEGF release; a similar response, mediated by IGF-II release, is observed following HIF1α stabilization. The existence of an autocrine loop is confirmed by its down-regulation following inactivation of IGF1R (using the IGF1R-specific tyrosine kinase inhibitor NVP-AEW541), STAT3 (transfecting the cells with an expression vector encoding a dominant negative form of STAT3), or HIF1 (using the small molecule inhibitor YC-1). The ability of NVP-AEW541 to block this circuit could be beneficial in suppressing the growth and angiogenic potential of hypoxic glial tumors.
We report on the synthesis of novel water-soluble (arene)RuII(Q)Cl and (arene)RuII(Q)(X)BF4 compounds (arene = p-cymene, benzene, hexamethylbenzene; HQ = 1,3-dimethyl-4-R-(CO)-5-pyrazolone, HQMe, R ...= methyl, HQPh, R = phenyl, HQNaph, R = naphthyl; X = H2O, 9-ethylguanine), and their in vitro antitumor activity toward the cell lines MCF7 (HTB-22, human breast adenocarcinoma), HCT116 (CCL-247, human colorectal carcinoma), A2780 (human ovarian carcinoma), A549 (CCL-185, human lung carcinoma), and U87 MG (HTB-1, human glioblastoma). The X-ray crystal structures of two complexes were determined. One of them, {chlorido-(p-cymene)-(1,3-dimethyl-4-(1-naphthoyl)-pyrazolon-5-atoruthenium(II)}, was also studied with density functional theory methods and was selected for docking on a DNA octamer showing intercalation between DNA bases by the naphthyl moiety and for Ru–N7(guanine) bonding.
Purpose
Peripheral fatigue involves electrochemical and mechanical mechanisms. An electromyographic, mechanomyographic and force combined approach may permit a kinetic evaluation of the changes at ...the synaptic, skeletal muscle fiber, and muscle–tendon unit level during a fatiguing stimulation.
Methods
Surface electromyogram, mechanomyogram, force and stimulation current were detected from the
gastrocnemius medialis
muscle in twenty male participants during a fatiguing stimulation (twelve blocks of 35 Hz stimulations, duty cycle 9 s on/1 s off, duration 120 s). The total electromechanical delay and its three components (between stimulation current and electromyogram, synaptic component; between electromyogram and mechanomyogram signal onset, muscle fiber electrochemical component, and between mechanomyogram and force signal onset, mechanical component) were calculated. Interday reliability and sensitivity were determined.
Results
After fatigue, peak force decreased by 48% (
P
< 0.05) and the total electromechanical delay and its synaptic, electrochemical and mechanical components lengthened from 25.8 ± 0.9, 1.47 ± 0.04, 11.2 ± 0.6, and 13.1 ± 1.3 ms to 29.0 ± 1.6, 1.56 ± 0.05, 12.4 ± 0.9, and 17.2 ± 0.6 ms, respectively (
P
< 0.05). During fatigue, the total electromechanical delay and the mechanical component increased significantly after the 40th second, and then remained stable. The synaptic and electrochemical components lengthened significantly after the 20th and 30th second, respectively. Interday reliability was high to very high, with an adequate level of sensitivity.
Conclusions
The kinetic evaluation of the delays during the fatiguing stimulation highlighted different onsets and kinetics, with the events at synaptic level being the first to reveal a significant elongation, followed by those at the intra-fiber level. The mechanical events, which were the most affected by fatigue, were the last to lengthen.
Background A ketogenic diet (KD) is a nutritional approach, usually adopted for weight loss, that restricts daily carbohydrates under 30 g/day. KD showed contradictory results on sport performance, ...whilst no data are available on team sports. We sought to investigate the influence of a KD on different parameters in semi-professional soccer players. Methods Subjects were randomly assigned to a iso-protein (1.8 g/Kg body weight/day) ketogenic diet (KD) or western diet (WD) for 30 days. Body weight and body composition, resting energy expenditure (REE), respiratory exchange ratio (RER), cross sectional area (CSA) and isometric muscle strength of quadriceps, counter movement jump (CMJ) and yoyo intermittent recovery test time were measured. Results There was a significantly higher decrease of body fat (p = 0.0359), visceral adipose tissue (VAT) (p = 0.0018), waist circumference (p = 0.0185) and extra-cellular water (p = 0.0060) in KD compared to WD group. Lean soft tissue, quadriceps muscle area, maximal strength and REE showed no changes in both groups. RER decreased significantly in KD (p = 0.0008). Yo-yo intermittent test improved significantly (p < 0.0001) in both groups without significant differences between groups. CMJ significantly improved (p = 0.0021) only in KD. Conclusions This is the first study investigating the effects of a KD on semi-professional soccer players. In our study KD athletes lost fat mass without any detrimental effects on strength, power and muscle mass. When the goal is a rapid weight reduction in such athletes, the use of a KD should be taken into account. Trial registration registered retrospectively on Clinical Trial registration number NCT04078971. Keywords: Ketogenic diet, Soccer, Body composition, Yo-yo intermittent test, Muscle cross sectional area, Metabolism
Stretch-shortening type actions are characterized by lengthening of the pre-activated muscle-tendon unit (MTU) in the eccentric phase immediately followed by muscle shortening. Under 1 g, ...pre-activity before and muscle activity after ground contact, scale muscle stiffness, which is crucial for the recoil properties of the MTU in the subsequent push-off. This study aimed to examine the neuro-mechanical coupling of the stretch-shortening cycle in response to gravity levels ranging from 0.1 to 2 g. During parabolic flights, 17 subjects performed drop jumps while electromyography (EMG) of the lower limb muscles was combined with ultrasound images of the gastrocnemius medialis, 2D kinematics and kinetics to depict changes in energy management and performance. Neuro-mechanical coupling in 1 g was characterized by high magnitudes of pre-activity and eccentric muscle activity allowing an isometric muscle behavior during ground contact. EMG during pre-activity and the concentric phase systematically increased from 0.1 to 1 g. Below 1 g the EMG in the eccentric phase was diminished, leading to muscle lengthening and reduced MTU stretches. Kinetic energy at take-off and performance were decreased compared to 1 g. Above 1 g, reduced EMG in the eccentric phase was accompanied by large MTU and muscle stretch, increased joint flexion amplitudes, energy loss and reduced performance. The energy outcome function established by linear mixed model reveals that the central nervous system regulates the extensor muscles phase- and load-specifically. In conclusion, neuro-mechanical coupling appears to be optimized in 1 g. Below 1 g, the energy outcome is compromised by reduced muscle stiffness. Above 1 g, loading progressively induces muscle lengthening, thus facilitating energy dissipation.
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