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Cell Death & Disease Jun 2024Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the...
Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the transcriptional differences between different muscle fiber types remain unclear. Here, we demonstrate distinct responses of fast/glycolytic fibers and slow/oxidative fibers to aging and obesity. We found that in muscles dominated by oxidative fibers, the proportion of oxidative fibers remains unchanged during aging and obesity. However, in muscles dominated by glycolytic fibers, despite the low content of oxidative fibers, a significant decrease in proportion of oxidative fibers was observed. Consistently, our study uncovered that during aging and obesity, fast/glycolytic fibers specifically increased the expression of genes associated with muscle atrophy and inflammation, including Dkk3, Ccl8, Cxcl10, Cxcl13, Fbxo32, Depp1, and Chac1, while slow/oxidative fibers exhibit elevated expression of antioxidant protein Nqo-1 and downregulation of Tfrc. Additionally, we noted substantial differences in the expression of calcium-related signaling pathways between fast/glycolytic fibers and slow/oxidative fibers in response to aging and obesity. Treatment with a calcium channel inhibitor thapsigargin significantly increased the abundance of oxidative fibers. Our study provides additional evidence to support the transcriptomic differences in muscle fiber types under pathophysiological conditions, thereby establishing a theoretical basis for modulating muscle fiber types in disease treatment.
Topics: Aging; Obesity; Animals; Gene Expression Profiling; Glycolysis; Male; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Transcriptome; Muscle Fibers, Slow-Twitch; Humans
PubMed: 38942747
DOI: 10.1038/s41419-024-06851-y -
Journal of Lipid Research Jun 2024Increasing evidence hints that DNA hypermethylation may mediate the pathogenic response to cardiovascular risk factors. Here, we tested a corollary of that hypothesis,...
Increasing evidence hints that DNA hypermethylation may mediate the pathogenic response to cardiovascular risk factors. Here, we tested a corollary of that hypothesis, i.e., that the DNA methyltransferase inhibitor decitabine (Dec) ameliorates the metabolic profile of mice fed a moderately high-animal fat and protein diet (HAFPD), a proxy of cardiovascular risk-associated Western-type diet. HAFPD-fed mice were exposed to Dec or vehicle for eight weeks (8W set, 4-32/group). To assess any memory of past exposure to Dec, we surveyed a second mice set treated as 8W but HAFPD-fed for further eight weeks without any Dec (16W set, 4-20/group). In 8W, Dec markedly reduced HAFPD-induced body weight gain in females, but marginally in males. Characterization of females revealed that Dec augmented skeletal muscle lipid content, while decreasing liver fat content and increasing plasma non-esterified fatty acids, adipose insulin resistance, and -although marginally- whole blood acylcarnitines, compared to HAFPD alone. Skeletal muscle mitochondrial DNA copy number was higher in 8W mice exposed to HAFPD and Dec, or in 16W mice fed HAFPD only, relative to 8W mice fed HAFPD only, but Dec induced a transcriptional profile indicative of ameliorated mitochondrial function. Memory of past Dec exposure was tissue-specific and sensitive to both duration of exposure to HAFPD and age. In conclusion, Dec redirected HAFPD-induced lipid accumulation towards the skeletal muscle, likely due to augmented mitochondrial functionality and increased lipid demand. As caveat, Dec induced adipose insulin resistance. Our findings may help identifying strategies for prevention and treatment of lipid dysmetabolism.
PubMed: 38942113
DOI: 10.1016/j.jlr.2024.100586 -
Physics in Medicine and Biology Jun 2024A major challenge in treatment of tumors near skeletal muscle is defining the target volume for suspected tumor invasion into the muscle. This study develops a framework...
A major challenge in treatment of tumors near skeletal muscle is defining the target volume for suspected tumor invasion into the muscle. This study develops a framework that generates radiation target volumes with muscle fiber orientation directly integrated into their definition. The framework is applied to nineteen sacral tumor patients with suspected infiltration into surrounding muscles. Approach. To compensate for the poor soft-tissue contrast of CT images, muscle fiber orientation is derived from cryo-images of two cadavers from the Human Visible Project (VHP). The approach consists of (a) detecting image gradients in the cadaver images representative of muscle fibers, (b) mapping this information onto the patient image, and (c) embedding the muscle fiber orientation into an expansion method to generate patient-specific clinical target volumes (CTV). The validation tested the consistency of image gradient orientation across VHP subjects for the piriformis, gluteus maximus, paraspinal, gluteus medius, and gluteus minimus muscles. The model robustness was analyzed by comparing CTVs generated using different VHP subjects. The difference in shape between the new CTVs and standard CTV was analyzed for clinical impact. Main results. Good agreement was found between the image gradient orientation across VHP subjects, as the voxel-wise median cosine similarity was at least 0.86 (for the gluteus minimus) and up to 0.98 for the piriformis. The volume and surface similarity between the CTVs generating from different VHP subjects was on average at least 0.95 and 5.13 mm for the Dice Similarity Coefficient and the Hausdorff 95% Percentile Index, showing excellent robustness. Finally, compared to the standard CTV with different margins in muscle and non-muscle tissue, the new CTV margins are reduced in muscle tissue depending on the chosen clinical margins. Significance. This study implements a method to integrate muscle fiber orientation into the target volume without the need for additional imaging.
PubMed: 38942035
DOI: 10.1088/1361-6560/ad5d50 -
Scientific Reports Jun 2024In honey bees, circulation of blood (hemolymph) is driven by the peristaltic contraction of the heart vessel located in the dorsal part of the abdomen....
In honey bees, circulation of blood (hemolymph) is driven by the peristaltic contraction of the heart vessel located in the dorsal part of the abdomen. Chlorantraniliprole (CHL) is an insecticide of the anthranilic diamide class which main mode of action is to alter the function of intracellular Ca release channels (known as RyRs, for ryanodine receptors). In the honey bee, it was recently found to be more toxic when applied on the dorsal part of the abdomen, suggesting a direct cardiotoxicity. In the present study, a short-term exposure of semi-isolated bee hearts to CHL (0.1-10 µM) induces alterations of cardiac contraction. These alterations range from a slow-down of systole and diastole kinetics, to bradycardia and cardiac arrest. The bees heart wall is made of a single layer of semi-circular cardiomyocytes arranged concentrically all along the long axis of tube lumen. Since the heart tube is suspended to the cuticle through long tubular muscles fibers (so-called alary muscle cells), the CHL effects in ex-vivo heart preparations could result from the modulation of RyRs present in these skeletal muscle fibers as well as cardiomyocytes RyRs themselves. In order to specifically assess effects of CHL on cardiomyocytes, for the first time, intact heart cells were enzymatically dissociated from bees. Exposure of cardiomyocytes to CHL induces an increase in cytoplasmic calcium, cell contraction at the highest concentrations and depletion of intracellular stores. Electrophysiological properties of isolated cardiomyocytes were described, with a focus on voltage-gated Ca channels responsible for the cardiac action potentials depolarization phase. Two types of Ca currents were measured under voltage-clamp. Exposure to CHL was accompanied by a decrease in voltage-activated Ca currents densities. Altogether, these results show that chlorantraniliprole can cause cardiac defects in honey bees.
Topics: Animals; Bees; ortho-Aminobenzoates; Myocytes, Cardiac; Insecticides; Cardiotoxicity; Calcium; Myocardial Contraction; Heart; Ryanodine Receptor Calcium Release Channel; Diamide
PubMed: 38942905
DOI: 10.1038/s41598-024-65007-2 -
Science Advances Jun 2024Rotator cuff repair surgeries fail frequently, with 20 to 94% of the 600,000 repairs performed annually in the United States resulting in retearing of the rotator cuff....
Rotator cuff repair surgeries fail frequently, with 20 to 94% of the 600,000 repairs performed annually in the United States resulting in retearing of the rotator cuff. The most common cause of failure is sutures tearing through tendons at grasping points. To address this issue, we drew inspiration from the specialized teeth of snakes of the Pythonoidea superfamily, which grasp soft tissues without tearing. To apply this nondamaging gripping approach to the surgical repair of tendon, we developed and optimized a python tooth-inspired device as an adjunct to current rotator cuff suture repair and found that it nearly doubled repair strength. Integrated simulations, 3D printing, and ex vivo experiments revealed a relationship between tooth shape and grasping mechanics, enabling optimization of the clinically relevant device that substantially enhances rotator cuff repair by distributing stresses over the attachment footprint. This approach suggests an alternative to traditional suturing paradigms and may reduce the risk of tendon retearing after rotator cuff repair.
Topics: Animals; Rotator Cuff; Boidae; Rotator Cuff Injuries; Tooth; Suture Techniques; Biomechanical Phenomena; Humans; Printing, Three-Dimensional
PubMed: 38941456
DOI: 10.1126/sciadv.adl5270 -
Medicine Jun 2024Combining hydromorphone with ropivacaine in ultrasound-guided erector spinae plane blocks enhances postoperative analgesia and reduces interleukin-6 expression in breast... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Combining hydromorphone with ropivacaine in ultrasound-guided erector spinae plane blocks enhances postoperative analgesia and reduces interleukin-6 expression in breast surgery patients.
METHODS
In this study, breast cancer patients undergoing modified radical mastectomy were randomized into 3 groups for anesthesia (30 patients in each group): standard general (group C), Erector Spinae Plane Block (ESPB) with ropivacaine (group R), and ESPB with ropivacaine plus hydromorphone (group HR). Diagnosis: Breast cancer patients. Postsurgery, pain levels, IL-6, anesthetic doses, additional analgesia needs, and recovery milestones were compared to evaluate the efficacy of the ESPB enhancements.
RESULTS
The 3 groups were not significantly different in baseline characteristics, operation time, number of cases with postoperative nausea, and serum IL-6 concentrations at T1 (the time of being returned to the ward after surgery). At T2 (at 6:00 in the next morning after surgery), the serum IL-6 concentration in group HR was significantly lower than that in groups R and C (P < .05); the intraoperative doses of remifentanil, sufentanil, and propofol were significantly lower in groups HR and R than those in group C (P < .05); Groups HR and R had significantly lower visual analog scale scores at T3 (4 hours postoperatively), T4 (12 hours postoperatively), and T5 (24 hours postoperatively) than those in group C (P < .05); the proportions of patients receiving postoperative remedial analgesia were significantly lower in groups HR and R than in group C (P < .05); groups HR and R had significantly lower proportions of patients with postoperative nausea than group C (P < .05); the time to the first anal exhaust and the time to the first ambulation after surgery were significantly shorter in groups HR and R than those in group C (P < .05).
CONCLUSION
Hydromorphone combined with ropivacaine for ESPB achieved a greater postoperative analgesic effect for patients receiving MRM under general anesthesia. The combined analgesia caused fewer adverse reactions and inhibited the expression level of the inflammatory factor IL-6 more effectively, thereby facilitating postoperative recovery. ESPB using hydromorphone with ropivacaine improved pain control post-MRM, reduced adverse effects, and more effectively suppressed IL-6, enhancing recovery.
Topics: Humans; Ropivacaine; Female; Hydromorphone; Middle Aged; Nerve Block; Pain, Postoperative; Prospective Studies; Anesthetics, Local; Breast Neoplasms; Mastectomy, Modified Radical; Analgesics, Opioid; Adult; Interleukin-6; Paraspinal Muscles; Ultrasonography, Interventional; Drug Therapy, Combination; Pain Measurement
PubMed: 38941366
DOI: 10.1097/MD.0000000000038758 -
Japanese Journal of Clinical Oncology Jun 2024Sarcopenic obesity (SO) affects outcomes in various malignancies. However, its clinical significance in patients undergoing neoadjuvant chemotherapy (NAC) for locally...
BACKGROUND
Sarcopenic obesity (SO) affects outcomes in various malignancies. However, its clinical significance in patients undergoing neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (LAGC) remains unclear. This study investigated the impact of pre- and post-NAC SO on postoperative morbidity and survival.
METHODS
Data from 207 patients with LAGC, who underwent NAC followed by radical gastrectomy between January 2010 and October 2019, were reviewed. Skeletal muscle mass and visceral fat area were measured pre- and post-NAC using computed tomography to define sarcopenia and obesity, the coexistence of which was defined as SO.
RESULTS
Among the patients, 52 (25.1%) and 38 (18.4%) developed SO before and after NAC, respectively. Both pre- (34.6%) and post- (47.4%) NAC SO were associated with the highest postoperative morbidity rates; however, only post-NAC SO was an independent risk factor for postoperative morbidity [hazard ratio (HR) = 9.550, 95% confidence interval (CI) = 2.818-32.369; P < .001]. Pre-NAC SO was independently associated with poorer 3-year overall [46.2% vs. 61.3%; HR = 1.258 (95% CI = 1.023-1.547); P = .049] and recurrence-free [39.3% vs. 55.4%; HR 1.285 (95% CI 1.045-1.579); P = .017] survival.
CONCLUSIONS
Pre-NAC SO was an independent prognostic factor in patients with LAGC undergoing NAC; post-NAC SO independently predicted postoperative morbidity.
PubMed: 38941323
DOI: 10.1093/jjco/hyae080 -
Diabetes Care Jun 2024The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the...
SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study.
OBJECTIVE
The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET).
RESEARCH DESIGN AND METHODS
In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups.
RESULTS
A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.01), an effect observed in both gray and white matter regions.
CONCLUSIONS
Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.
PubMed: 38941156
DOI: 10.2337/dc24-0470 -
Skeletal Radiology Jun 2024Fatty infiltration of skeletal muscle (Myosteatosis) is associated with increased frailty, decreased muscle and mobility function, which seems fairly prevalent in...
OBJECTIVE
Fatty infiltration of skeletal muscle (Myosteatosis) is associated with increased frailty, decreased muscle and mobility function, which seems fairly prevalent in multiple myeloma (MM) patients. This study aimed to determine the prognostic value of myosteatosis assessed by CT for progression-free survival (PFS) and overall survival (OS).
MATERIALS AND METHODS
This IRB-approved cohort study included patients with newly diagnosed MM who were treated at a single university hospital and received CT at baseline. Geriatric assessment was performed via International Myeloma Working Group frailty score and Revised Myeloma Comorbidity Index. Myosteatosis was determined through measurement of paravertebral muscle radiodensity. Statistical analyses included uni- and multivariable Cox proportional hazard models and the Kaplan-Meier-method.
RESULTS
A total of 226 newly diagnosed MM patients (median age: 65 years [range: 29-89], 63% males, mean BMI: 25 [14-42]) were analyzed. The prevalence of myosteatosis was 51%. Muscle radiodensity was significantly decreased in individuals with International Staging System stage III vs. I (p < 0.001), indicating higher fatty muscle infiltration in patients with advanced disease. Both PFS and OS were significantly decreased in patients with myosteatosis (PFS: median 32.0 months (95% CI 20.5.5-42.2) vs. 66.4 months without myosteatosis (95% CI 42.5-not reached), p < .001); OS: median 58.6 (95% CI 51.3-90.2) vs. not reached, p < .001). Myosteatosis remained an independent predictor of OS in multivariable analyses (HR: 1.98; 95%-CI: 1.20-3.27).
CONCLUSION
Myosteatosis seems fairly prevalent in patients with newly diagnosed MM and associated with impaired overall survival. Prospective clinical trials are required to better understand the role of myosteatosis in MM patients.
PubMed: 38940940
DOI: 10.1007/s00256-024-04735-y -
Clinical Oral Investigations Jun 2024This study aimed to assess whether awake bruxism and masticatory muscle activity could be related to external root resorption (ERR) in second molars adjacent to impacted...
Is there a relationship between the presence of external root resorption in second molars adjacent to impacted mandibular third molars with awake bruxism and masticatory muscle activity?
OBJECTIVES
This study aimed to assess whether awake bruxism and masticatory muscle activity could be related to external root resorption (ERR) in second molars adjacent to impacted mandibular third molars.
MATERIALS AND METHODS
Sixty patients, with requests for a cone-beam, computed tomography, were divided into two groups: ERR (patients with ERR in the second molar, n = 30), and control group (n = 30). Awake bruxism was assessed through the Oral Behaviors Checklist (OBC) and an ecological momentary assessment (EMA). Surface electromyography (EMG) was used to assess the masseter and anterior temporal muscle function. Normality and homogeneity of variances were demonstrated. Descriptive analysis was performed, using the T-test and Chi-square test to compare the characteristics of the groups. A multiple regression model was performed.
RESULTS
The ERR group presented more non-functional oral activities related to awake bruxism than the control group, according to OBC (p = 0.027) and EMA (p = 0.035). In addition, the ERR group had higher EMG activity than the control group in rest and isotonic protocols (p < 0.05).
CONCLUSIONS
Awake bruxism and greater masticatory muscle activity seem to be related to the presence of ERR in second molars adjacent to impacted mandibular third molars.
CLINICAL RELEVANCE
The results of the present study can reinforce the theory that triggering ERR in the second molars adjacent to impacted mandibular third molars may be related to mechanical forces coming from the masticatory function.
Topics: Humans; Electromyography; Molar, Third; Female; Male; Tooth, Impacted; Adult; Cone-Beam Computed Tomography; Root Resorption; Molar; Bruxism; Masticatory Muscles; Mandible
PubMed: 38940883
DOI: 10.1007/s00784-024-05775-3