Muscle Dysfunction Research Articles

Sex-dependent interplay of phosphate and inflammation on muscle strength irrespective of muscle mass in middle-aged and older adults

BackgroundElevated circulatory phosphate levels are linked to age-related muscle dysfunction, yet the mechanisms remain unclear. This study investigated the hypothesis that inflammation plays a role in connecting elevated phosphate levels to muscular dysfunction in middle-aged and older individuals and explored potential sex-based differences in these associations. MethodsThe study, based on the I-Lan Longitudinal Aging Study Cohort, analyzed individuals' serum phosphate and hsCRP levels. Sex-specific analyses explored links between circulatory phosphate, inflammation, and muscle profiles (mass, handgrip strength, and walking speed). The study also examined potential mediation or synergistic effects of inflammation in the circulatory phosphate-muscle relationship. ResultsThe study included 2006 participants (mean age: 65.5 ± 6.5 years; 49.8 % men). Women exhibited higher circulatory phosphate levels than men. Linear analyses revealed that higher phosphate levels were significantly associated with weaker handgrip strength but not with reduced muscle mass in both men and women. In women, circulatory phosphate was not associated with inflammation (hsCRP levels), while in men, higher phosphate levels were significantly associated with higher hsCRP levels. In men, a synergistic effect was observed, where the combination of high hsCRP and elevated phosphate levels had a more pronounced impact on reducing handgrip strength than either factor alone. ConclusionsThis study highlights a sex-specific association of inflammation in the mechanisms of hyperphosphatemia-related muscle weakness. The findings emphasize the importance of managing both hyperphosphatemia and chronic inflammation to mitigate their collective impact on muscle function, particularly in older men. Addressing these factors is crucial for promoting muscle health in later life.

JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle.

Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

Heat exposure promotes sarcopenia via gut microbiota-derived metabolites.

The unprecedented rise in global ambient temperatures in the last decade has significantly impacted human health, yet how heat exposure affects the development of sarcopenia remains enigmatic. Here, we demonstrate that chronic heat exposure induces skeletal muscle volume loss, leading to muscle strength and functional decline in mice. The microbiota composition of heat-exposed mice was analyzed using 16S ribosomal DNA analysis. Liquid chromatography-mass spectrometry (LC-MS) was used to explore the effects of heat exposure on the blood metabolome and to further analyze the correlation between blood metabolism and gut microbiota. Transplantation of microbiota from heat-exposed mice to germ-free mice was sufficient to increase adverse effects on skeletal muscle function in the host. Mechanistically, using an untargeted metabolomics strategy, we reveal that altered gut microbiota due to high temperatures is associated with elevated serum levels of homocitrulline. Homocitrulline causes mitochondrial dysfunction in myocytes by exacerbating ferroptosis levels. And Nrf2 activator (Oltipraz) supplementation alleviates muscle atrophy and dysfunction induced by heat exposure. Our findings reveal the detrimental effects of heat exposure on muscle function and provide new strategies for treating sarcopenia.

Titin hyper-phosphorylation in the peripheral skeletal muscle but not the diaphragm of HFpEF: association with muscle atrophy and dysfunction

Abstract Background Titin hypo-phosphorylation is an important regulatory mechanism for myocardial stiffness in heart failure with preserved ejection fraction (HFpEF). In contrast, a hyper-phosphorylation of titin in the peripheral skeletal muscle (SKM) was reported in mouse models exhibiting muscle atrophy. In former studies it, was shown that SKM atrophy occurs in HFpEF and is associated with muscle dysfunction and a fiber type shift from type I, towards type II fibers. However, these alterations were not seen in the diaphragm muscle (Dia) and a fiber type shift towards type I was documented. So far, no information about the phosphorylation status of titin is available for SKM and the Dia and its association with muscle dysfunction in HFpEF. Purpose To assess titin phosphorylation in SKM and Dia of a HFpEF animal model and to relate it to muscle function and atrophy. Methods To confirm the development of HFpEF echocardiography was performed in female ZSF1-lean (con, n=18) and ZSF1-obese rats (HFpEF, n=18) at the age of 32 weeks. Skeletal muscle function (soleus) was measured in an organ bath setting after the animals were sacrificed. Tissue of the tibialis anterior muscle (TA) and the diaphragm (Dia) was collected and fixed in formalin or snap frozen in liquid nitrogen. To detect titin expression homogenized TA and Dia tissue samples were resolved on a vertical agarose gel. Phosphorylated titin was detected by staining the gel with Pro-Q Diamond, whereas total titin was visualized using Sypro Ruby. Cross sectional area (CSA) of TA and Dia was quantified after Hematoxylin/eosin staining of tissue section. Myosin heavy chain (MHC) ubiquitination was assessed by western blot. Results Assessment of SKM function revealed significantly reduced maximal absolute (-12 %) and maximal specific force (-22 %) in HFpEF animals when compared to controls. In the TA a significantly reduced CSA was evident in HFpEF (1911±103 vs. 1394±103 µm2, p=0.002), whereas in the diaphragm an increased CSA was noted (438±11 vs. 560±18 µm2, p<0.001). In TA of HFpEF animals, the proportion of phosphorylated titin was significantly elevated whereas the total amount of titin was reduced (Fig. 1A, C). In addition, a significantly higher proportion of ubiquitinated MHC was detected (Figure 1E). However in the Dia these alterations were not observed, even a higher amount of total titin was seen (Fig. 1B, D, F). Furthermore, a significant negative correlation between phosphorylated titin and absolute force (r=-0.461, p=0.035, Fig. 2A) as well as specific force (r=-0.693, p=0.0005, Fig. 2B) was evident. Conclusion In contrast to the heart, the TA showed a titin hyper-phosphorylation in HFpEF, going along with a degradation of total titin. This hyper-phosphorylation could be correlated with a loss of force in the SKM. Additionally a higher ubiquitination of MHC was prevalent in the TA, which may be connected to molecular remodeling and fiber type shift towards a more glycolytic type.

Relationship of cumulative low-density lipoprotein cholesterol with atherosclerosis

Abstract Background The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. Objective The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). Methods This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg･year/dL, 4000-4999 mg･year/dL, 5000-5999 mg･year/dL, and ≥6000 mg･year/dL. Results The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg･year/dL group was significantly higher than the odds ratios in the other groups (Figure 1A). The odds ratio of the lower quartile of NID in the <4000 mg・year/dL group was significantly higher than the odds ratios in the 5000-5999 mg･year/dL and ≥6000 mg･year/dL groups (Figure 1B). The odds ratio of the prevalence of CCA plaque in the <4000 mg・year/dL group was significantly higher than that in the ≥6000 mg･year/dL group (Figure 1C). Conclusions Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg・year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg･year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg･year/dL.Graphical abstractFigure 1

The effect of biocide chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) mixture on C2C12 muscle cell damage attributed to mitochondrial reactive oxygen species overproduction and autophagy activation

ABSTRACT The mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT) is a biocide widely used as a preservative in various commercial products. This biocide has also been used as an active ingredient in humidifier disinfectants in South Korea, resulting in serious health effects among users. Recent evidence suggests that the underlying mechanism of CMIT/MIT-initiated toxicity might be associated with defects in mitochondrial functions. The aim of this study was to utilize the C2C12 skeletal muscle model to investigate the effects of CMIT/MIT on mitochondrial function and relevant molecular pathways associated with skeletal muscle dysfunction. Data demonstrated that exposure to CMIT/MIT during myogenic differentiation induced significant mitochondrial excess production of reactive oxygen species (ROS) and a decrease in intracellular ATP levels. Notably, CMIT/MIT significantly inhibited mitochondrial oxidative phosphorylation (Oxphos) and reduced mitochondrial mass at a lower concentration than the biocide amount, which diminished the viability of myotubes. CMIT/MIT induced activation of autophagy flux and decreased protein expression levels of myosin heavy chain (MHC). Taken together, CMIT/MIT exposure produced damage in C2C12 myotubes by impairing mitochondrial bioenergetics and activating autophagy. Our findings contribute to an increased understanding of the underlying mechanisms associated with CMIT/MIT-induced adverse skeletal muscle health effects.

Dynamical network-based evaluation for neuromuscular dysfunction in stroke-induced hemiplegia during standing

BackgroundA given movement requires precise coordination of multiple muscles under the control of center nervous system. However, detailed knowledge about the changing characteristics of neuromuscular control for multi-muscle coordination in post-stroke hemiplegic patients during standing is still lacking. This study aimed to investigate the hemiplegia-linked neuromuscular dysfunction during standing from the perspective of multi-muscle dynamical coordination by utilizing a novel network approach – weighted recurrence network (WRN).MethodsTen male hemiplegic patients with first-ever stroke and 10 age-matched healthy male adults were instructed to stand on a platform quietly for 30 s with eyes opened and eyes closed, respectively. The WRN was constructed based on the surface electromyography signals of 16 muscles from trunk, hips, thighs and calves. Relevant topological parameters, including clustering coefficient (C) and average shortest path length (L), were extracted to evaluate the dynamical coordination of multiple muscles. A measure of node centrality in network theory, degree of centrality (DC), was innovatively introduced to assess the contribution of single muscle in the multi-muscle dynamical coordination. The standing-related assessment metric, center of pressure (COP), was provided by the platform directly.ResultsResults showed that the post-stroke hemiplegic patients stood with remarkably higher similarity of muscle activation and more coupled intermuscular dynamics, characterized by higher C and lower L than the healthy subjects (p < 0.05). The DC values and rankings of back, hip and calf muscles on the affected side were significantly decreased, whereas those on the unaffected side were significantly increased in hemiplegia group compared with the healthy group (p < 0.05). Without visual feedback, subjects exhibited enhanced muscle coordination and increased muscle involvement (p < 0.05). A decrease in C and an increase in L of WRN were observed with decreased COP areas (p < 0.05).ConclusionsThese findings revealed that stroke-induced hemiplegia could significantly influence the neuromuscular control, which was manifested as more coupled intermuscular dynamics, abnormal deactivation of muscles on affected side and compensation of muscles on unaffected side from the perspective of multi-muscle coordination. Enhanced multi-muscle dynamical coordination was strongly associated with impaired postural control. This study provides a novel analytical tool for evaluation of neuromuscular dysfunction and specification of responsible muscles for impaired postural control in stroke-induced hemiplegic patients, and could be potentially applied in clinical practice.

Time-restricted feeding mediated modulation of microbiota leads to changes in muscle physiology in Drosophila obesity models.

Recent research has highlighted the essential role of the microbiome in maintaining skeletal muscle physiology. The microbiota influences muscle health by regulating lipid metabolism, protein synthesis, and insulin sensitivity. However, metabolic disturbances such as obesity can lead to dysbiosis, impairing muscle function. Time-restricted feeding (TRF) has been shown to mitigate obesity-related muscle dysfunction, but its effects on restoring healthy microbiomes remain poorly understood. This study utilizes 16S microbiome analysis and bacterial supplementation to investigate the bacterial communities influenced by TRF that may benefit skeletal muscle physiology. In wild-type and obese Drosophila models (axenic models devoid of natural microbial communities), the absence of microbiota influence muscle performance and metabolism differently. Specifically, axenic wild-type Drosophila exhibited reduced muscle performance, higher glucose levels, insulin resistance, ectopic lipid accumulation, and decreased ATP levels. Interestingly, in obese Drosophila (induced by a high-fat diet or predisposed obesity mutant Sk2), the absence of microbiota improved muscle performance, lowered glucose levels, reduced insulin resistance, and increased ATP levels. TRF was found to modulate microbiota composition, notably increasing Acetobacter pasteurianus (AP) and decreasing Staphylococcus aureus (SA) in both obesity models. Supplementation with AP improved muscle performance and reduced glucose and insulin resistance, while SA supplementation had the opposite effect. This study provides novel insights into the complex interactions between TRF, microbiota, and skeletal muscle physiology in different Drosophila models.

Pathological Characteristics of Muscle Rejection and Dysfunction in a Swine Vascularized Composite Allotransplantation Model and a Scoring Proposal: A Pilot Study.

Pathological Characteristics of Muscle Rejection and Dysfunction in a Swine Vascularized Composite Allotransplantation Model and a Scoring Proposal: A Pilot Study.

High-Flow Nasal Oxygen in Patients with Acute Hypercapnic Respiratory Failure: A Narrative Review of the Physiological Rationale and Clinical Evidence

Acute hypercapnic respiratory failure is a life-threatening condition caused by alveolar hypoventilation. It is mostly caused by an acute exacerbation of chronic obstructive pulmonary disease or conditions yielding muscle dysfunction. Noninvasive ventilation through a facemask is the cornerstone first-line strategy to support hypercapnic patients with acidemia, and current guidelines strongly recommend this intervention to improve survival and long-term clinical outcomes. Because of its benefits related to carbon dioxide washout from the upper airways and the enhanced comfort, high-flow nasal oxygen has been proposed as a respiratory support strategy in patients with hypercapnic respiratory failure, both as an alternative to and in combination with noninvasive ventilation. When compared to noninvasive ventilation as a first-line intervention, high-flow nasal oxygen shows a higher rate of failure. Hence, if not contraindicated, the use of noninvasive ventilation should be preferred. After the resolution of acidemia with noninvasive ventilation, high-flow nasal oxygen showed promising physiological effects compared to conventional oxygen. During weaning from mechanical ventilation in patients with or at risk of developing hypercapnia, high-flow nasal oxygen showed encouraging results, especially when applied alternating with sessions of noninvasive ventilation. Optimal settings of high-flow nasal oxygen in hypercapnic patients include the use of a smaller-size cannula, flows ranging between 30 and 40 L/min, and FiO2 adjusted to obtain SpO2 between 88% and 92%. Specific interfaces, such as asymmetric cannulas, may further enhance the benefits of a high flow in terms of carbon dioxide clearance. In this narrative review, we provide an updated overview of the physiological rationale and clinical evidence concerning the use of high-flow nasal oxygen in patients with acute hypercapnic respiratory failure.

Uncovering the Embryonic Origins of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the DMD gene, which encodes dystrophin. Despite its initial description in the late 19th century by French neurologist Guillaume Duchenne de Boulogne, and identification of causal DMD genetic mutations in the 1980s, therapeutics remain challenging. The current standard of care is corticosteroid treatment, which delays the progression of muscle dysfunction but is associated with significant adverse effects. Emerging therapeutic approaches, including AAV-mediated gene transfer, CRISPR gene editing, and small molecule interventions, are under development but face considerable obstacles. Although DMD is viewed as a progressive muscle disease, muscle damage and abnormal molecular signatures are already evident during fetal myogenesis. This early onset of pathology suggests that the limited success of current therapies may partly be due to their administration after aberrant embryonic myogenesis has occurred in the absence of dystrophin. Consequently, identifying optimal therapeutic strategies and intervention windows for DMD may depend on a better understanding of the earliest DMD disease mechanisms. As newer techniques are applied, the field is gaining increasingly detailed insights into the early muscle developmental abnormalities in DMD. A comprehensive understanding of the initial events in DMD pathogenesis and progression will facilitate the generation and testing of effective therapeutic interventions.

Screening of hub genes for sepsis-induced myopathy by weighted gene co-expression network analysis and protein-protein interaction network construction

Sepsis-induced myopathy is one of the serious complications of sepsis, which severely affects the respiratory and peripheral motor systems of patients, reduces their quality of life, and jeopardizes their lives, as evidenced by muscle atrophy, loss of strength, and impaired regeneration after injury. The pathogenesis of sepsis-induced myopathy is complex, mainly including cytokine action, enhances free radical production in muscle, increases muscle protein hydrolysis, and decreases skeletal muscle protein synthesis, etc. The above mechanisms have been demonstrated in existing studies. However, it is still unclear how the overall pattern of gene co-expression affects the pathological process of sepsis-induced myopathy. Therefore, we intend to identify hub genes and signaling pathways. Weighted gene co-expression network analysis was our main approach to study gene expression profiles: skeletal muscle transcriptome in ICU patients with sepsis-induced multi-organ failure (GSE13205). After data pre-processing, about 15,181 genes were used to identify 13 co-expression modules. Then, 16 genes (FEM1B, KLHDC3, GPX3, NIFK, GNL2, EBNA1BP2, PES1, FBP2, PFKP, BYSL, HEATR1, WDR75, TBL3, and WDR43) were selected as the hub genes including 3 up-regulated genes and 13 down-regulated genes. Then, Gene Set Enrichment Analysis was performed to show that the hub genes were closely associated with skeletal muscle dysfunction, necrotic and apoptotic skeletal myoblasts, and apoptosis in sepsis-induced myopathy. Overall, 16 candidate biomarkers were certified as reliable features for more in-depth exploration of sepsis-induced myopathy in basic and clinical studies.

Younger Age Is Associated With Pelvic Floor Muscle Dysfunction in Women With Urinary Symptoms.

Recent articles have highlighted the existence of pelvic floor myofascial dysfunction in women presenting with pelvic floor disorders. The aim of the study was to evaluate whether younger age is associated with pelvic floor muscle dysfunction in women with lower urinary tract symptoms, including urinary urgency, frequency, nocturia, and urinary incontinence. This retrospective cohort study included women seeking an initial outpatient urogynecology evaluation for urinary symptoms from 8/2018 to 2/2022. The primary outcome was the presence of pelvic floor muscle dysfunction, defined as a diagnosis of levator myalgia/spasm. Multivariable logistic regression was used to evaluate the association. Four hundred twenty-one women with lower urinary tract symptoms were included, and 115 (27.3%) were diagnosed with pelvic floor muscle dysfunction. Women with pelvic floor dysfunction were 13 years younger, less likely to report any incontinence (60% vs 71.9%, P = 0.026) and urgency incontinence (8.7% vs 17.3%, P = 0.04). There was no difference in reported urgency, frequency, or nocturia. Women with pelvic floor dysfunction were more likely to report dysuria (19.1% vs 9.5%, P = 0.012), dyspareunia (39% vs 7.5%, P < 0.001), vulvodynia (11.3% vs 2.3%, P < 0.001), and pelvic pain (25.2% vs 7.2%, P < 0.001). The odds of pelvic floor muscle dysfunction in women <40 years old was 2.34 times greater than women ≥40 years old, after adjusting for other factors (adjusted odds ratio 2.341, 95% confidence interval [1.102, 4.972]). Younger women with lower urinary tract symptoms were significantly more likely to have pelvic floor muscle dysfunction compared to older women with similar symptoms, even after controlling for other associated characteristics.

Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19.

Persistent skeletal muscle dysfunction in survivors of critical illness due to acute respiratory failure is common, but biological data elucidating underlying mechanisms are limited. The objective of this study was to elucidate the prevalence of skeletal muscle weakness and fatigue in survivors of critical illness due to COVID-19 and determine if cellular changes associate with persistent skeletal muscle dysfunction. A prospective observational study in two phases: 1) survivors of critical COVID-19 participating in physical outcome measures while attending an ICU Recovery Clinic at short-term follow-up and 2) a nested cohort of patients performed comprehensive muscle and physical function assessments with a muscle biopsy; data were compared with non-COVID controls. ICU Recovery Clinic and clinical laboratory. Survivors of critical COVID-19 and non-COVID controls. None. One hundred twenty patients with a median of 56 years old (interquartile range [IQR], 42-65 yr old), 43% female, and 33% individuals of underrepresented race attended follow-up 44 ± 17 days after discharge. Patients had a median Acute Physiology and Chronic Health Evaluation-II score of 24.0 (IQR, 16-29) and 98 patients (82%) required mechanical ventilation with a median duration of 14 days (IQR, 9-21 d). At short-term follow-up significant physical dysfunction was observed with 93% of patients reporting generalized fatigue and performing mean 218 ± 151 meters on 6-minute walk test (45% ± 30% of predicted). Eleven patients from this group agreed to participate in long-term assessment and muscle biopsy occurring a mean 267 ± 98 days after discharge. Muscle tissue from COVID exhibited a greater abundance of M2-like macrophages and satellite cells and lower activity of mitochondrial complex II and complex IV compared with controls. Our findings suggest that aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.

Non-invasive vagus nerve stimulation to reduce ileus after colorectal surgery: randomized feasibility trial and efficacy assessment (IDEAL Stage 2B).

Ileus is characterized by a period of intestinal dysmotility after surgery, leading to vomiting and constipation. In preclinical models, vagus nerve stimulation reduces intestinal inflammation and prevents smooth muscle dysfunction, accelerating the return of gut function. This study explored the feasibility of a definitive trial of non-invasive vagus nerve stimulation (nVNS) along with an early assessment of efficacy. A multicentre, randomized feasibility trial (IDEAL Stage 2B) of self-administered nVNS was performed. Patients undergoing colorectal surgery were randomized to nVNS or sham before and after surgery. Feasibility outcomes comprised assessments of recruitment, compliance, blinding and attrition. Clinical outcomes were measures of intestinal function and adverse events. All participants were followed up for 30 days. Interviews with patients and health professionals explored barriers to feasibility and perspectives around implementation. In all, 125 patients were approached about the study and 97 (77.6%) took part. Across all randomized groups, the median compliance to treatment was 19 out of 20 stimulations (interquartile range 17-20). The incidence of adverse events was similar across groups. In this unpowered feasibility study, the time taken for the return of gut function (such as first passage of stool) was similar between nVNS and sham treatments. According to interviews, patients were highly motivated to use the device because it provided them with an opportunity to engage actively in their care. Health professionals were highly driven to tackle the problem of ileus. Powered assessments of clinical efficacy are required to confirm or refute the promise of nVNS, as already demonstrated in preclinical models. This feasibility study concludes that a definitive randomized assessment of the clinical benefits of nVNS is desired and feasible.

CHANGES IN THE CONTENT AND ACTIVITY OF MUSCLE PROTEINS AS A MARKER IN THE CASE OF EXPOSURE TO IONIZING RADIATION IN ANIMALS

Objective. To find out the specifics of muscle tissue contraction under the conditions of exposure to low doses of ionizing radiation in parents and their irradiated offspring by evaluating changes in the content of contractile proteins and ATPase activity of skeletal and cardiac muscles. Methods. Experimental studies were conducted on 50 rats. Animals were randomized as follows: group 1 — intact sexually mature rats; 2 — sexually mature animals irradiated with a dose of 1.0 Gy; group 3 — monthold rats obtained from intact individuals; group 4 — month-old rat pups obtained from parents irradiated with a dose of 1.0 Gy; group 5 — month-old rats obtained from animals irradiated with a dose of 1.0 Gy, which were irradiated at the same dose. The results. Muscle dysfunction in irradiated offspring and parents is manifested by a decrease in the content of contractile proteins, functional dysfunction of the actomyosin bridge, and a decrease in the ATPase activity of contractile proteins. Marked muscle dysfunctions during the post-radiation time period may be the reason for the formation of orthopedic pathology in a significant contingent of irradiated persons. Conclusions. The expression of muscle dysfunction in the offspring of irradiated animals, which were also exposed to ionizing radiation, is greater than the corresponding processes in their irradiated parents, which indicates the mediation of muscle dysfunction in the second generation of irradiated animals by epigenetic mechanisms. Marked muscle dysfunctions during the post-radiation time period may be the reason for the formation of orthopedic pathology in a significant contingent of irradiated persons

Association between dynapenic obesity and risk of cardiovascular disease: The Hisayama study.

Dynapenic obesity is a condition characterized by high adiposity levels combined with muscle dysfunction. Although high adiposity and muscle loss/dysfunction are thought to synergistically increase the risk of cardiovascular disease (CVD), few studies have addressed the association between dynapenic and sarcopenic obesity and CVD. We aimed to investigate the association of dynapenic obesity with incident CVD events using the data from a population-based prospective longitudinal study in Japan. A total of 2490 community-dwelling Japanese aged 40-79years (42.5% males, mean age 57.7±10.6years) without a history of CVD were followed up for a median of 24years. Handgrip strength was classified as low, medium, or high by age- and sex-specific tertiles. Body mass index (BMI) levels were categorized as lean (<18.5kg/m2), normal (18.5-24.9kg/m2), or obese (≥25.0kg/m2). Dynapenic obesity was defined as having both low handgrip strength and obesity. The outcomes were defined as the first-ever development of CVD (defined as stroke or coronary heart disease). The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the development of CVD were estimated using a Cox proportional hazards model, in which participants with high handgrip strength and normal BMI were used as a reference group. Mediation analyses used serum high-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment for insulin resistance (HOMA-IR) as mediators. During the follow-up period, 482 participants developed CVD events (324 cases of stroke and 209 of coronary heart disease). The multivariable-adjusted risk of CVD increased significantly among participants with dynapenic obesity compared with the reference group (HR 1.49, 95% CI 1.03-2.17). An analysis by age groups showed a further increase in the risk of CVD among participants with dynapenic obesity aged less than 65years (HR 1.66, 95% CI 1.04-2.65). In mediation analyses for participants aged less than 65years, serum hs-CRP was shown to be a significant mediator explaining 13.8% of the association between dynapenic obesity and the development of CVD, while HOMA-IR explained 12.2% of this relationship. Dynapenic obesity was a significant risk factor for the development of CVD in a general Japanese population. This association was more pronounced among those aged <65years. Inflammation, and possibly glucose metabolism, might partly mediate this association. Our findings suggest that preventing muscle dysfunction as well as appropriate weight control, especially in middle-age, are important for preventing the development of CVD.

Mechanical Stress-Oxidative Stress Axis: Biological Basis in the Vaginal Wall and Pelvic Floor Muscles of Rats with Simulated Birth Injury.

Vaginal delivery and resulting pelvic floor muscle (PFM) dysfunction are significant risk factors for pelvic floor dysfunction (PFD). Despite this, the biological basis underlying PFD after childbirth remain unclear. This study was aimed at assessing the early response of the vaginal wall and PFM to simulated birth injury (SBI) in rats. Forty female Sprague-Dawley rats were divided into four groups: control (sham operation), and 1, 4, and 14days post-injury. In the SBI groups, a catheter was inserted into the vagina with 130g of weight attached to the end, and the balloon was inflated to 5ml for 2h. Evaluation of vaginal tissues and PFMs included histological, immunohistochemical, Western blot, and uniaxial biomechanical testing. In the vaginal wall, the SBI group showed significantly lower COL1A1 expression and higher MMP-2 and MMP-9 expression. At 4 and 14days post-injury, there was a significant decrease in PFM fiber area and increased collagen content. The SBI group also exhibited significant increases in the expression of Nrf2, NQO1, HO-1, and SOD-2, indicating involvement of oxidative stress in both the vaginal wall and PFMs. Protein expression of Pax7 and MyoG, as well as the number of fibers with centralized nuclei, continued to increase significantly after SBI. Additionally, the vaginal wall of the SBI group showed a decreasing trend in tensile strength and elastic modulus, with a greater ultimate strain. Extracellular matrix remodeling, oxidative stress, decreased biomechanical properties, and muscle dysmyogenesis may collectively contribute to increased susceptibility to PFD development.

8068 Beneficial Effects of a Personalized Exercise Program for Patients with Cushing's Disease and Acromegaly After Biochemical Control

Abstract Disclosure: E. Valassi: None. L. Martel-Duguech: None. H. Bascuñana: None. V. Priego-Corredor: None. J. Viñals-Ribé: None. O. González-Viñuela: None. T. Caparrós-Pons: None. S.M. Webb: None. Background: Patients with Cushing’s disease (CD) in remission and controlled acromegaly (ACRO) present with residual metabolic derangements, muscle dysfunction, and poor quality of life (QoL). Although exercise is known to exert positive effects on psychophysical health in several conditions, evidence demonstrating its potential benefits in pituitary diseases is scanty. Main hypothesis: A personalized program of combined (aerobic and resistance training) exercise lasting 12 weeks improves cardiometabolic parameters, body composition, physical performance and QoL in patients with CD in remission and controlled ACRO. Methodology: Ten female patients with CD in remission [mean (±SD) age, 59±4 years, mean (±SD) BMI, 35±2 Kg/m2, median (IQR) duration of remission, 5(4) years] and 10 male patients with controlled ACRO [mean (±SD) age, 53±9 years, mean (±SD) BMI, 27±4 Kg/m2, median (IQR) duration of control, 6(3) years] underwent a 12-week, structured, personalized program of combined aerobic and resistance exercise, under the supervision of professional trainers. We evaluated the following parameters at baseline and within 72 hours after the completion of the exercise program: blood pressure (BP), BMI, waist and neck circumferences; physical performance (gait speed, hand grip strength, 30-Second Chair Stand; Timed “Up and Go”); lumbar and femoral bone mineral density (BMD) and body composition, using dual x-ray absorptiometry (DXA); muscle thickness (cm) at the middle and distal third of rectus femoris (RF) and vastus intermedius (VI) on both sides, using muscle ultrasound scans in the transverse plane (Philips Affiniti 70; The Netherlands); quality of life (QoL), using the questionnaires CushingQoL in CD patients and AcroQoL in ACRO patients. Major results: After completion of the exercise program, CD patients had lower diastolic BP and waist circumference as compared with baseline (p&amp;lt;0.05). Physical performance globally improved (p&amp;lt;0.01 for all function tests). Femoral BMD was higher, percentage of lean mass increased while trunk fat decreased (p&amp;lt;0.01). RF and VI muscle thickness was greater at both the middle and distal third on the right side (p&amp;lt;0.01), and at the distal third on the left as compared with baseline (p&amp;lt;0.05). ACRO patients had a lower systolic BP as compared with baseline. Gait speed and hand grip strength increased while performance on the 30-Second Chair Stand improved (p&amp;lt;0.05). Muscle thickness at the middle third of the right RF was greater as compared with baseline (p&amp;lt;0.05). QoL was unchanged in both CS and ACRO patients at the end of the program. Conclusions: A customized exercise program promotes beneficial cardiometabolic and muscle changes in patients with CD and ACRO and, therefore, should be offered in a specialized pituitary clinic, within an integrated multidisciplinary team approach. Study financed by ISCIII research project number FIS PI21/01223 Presentation: 6/1/2024

Whole-exome sequencing reveals the genetic causes and modifiers of moyamoya syndrome

Moyamoya vasculopathy secondary to various genetic disorders is classified as moyamoya syndrome (MMS). Recent studies indicate MMS occurs due to a combination of genetic modifiers and causative mutations for the primary genetic disorders. We performed whole-exome sequencing (WES) in 13 patients with various genetic disorders who developed MMS. WES successfully revealed the genetic diagnoses of neurofibromatosis type 1 (NF-1), Down syndrome, multisystemic smooth muscle dysfunction syndrome, Noonan syndrome, and alpha thalassemia. The previously reported modifier genes, RNF213 and MRVI1, were confirmed in the NF-1 and Down syndrome cases. Further analysis revealed rare hypomorphic variants in the causative genes of the primary disorders underlying MMS, such as Alagille syndrome and Rasopathies, conferred susceptibility to MMS. Genes involved in the development of pulmonary arterial hypertension (PAH), such as ABCC8 and BMPR2, were also identified as potential modifiers. The rare variants in the MMS and PAH genes were significantly enriched in the eight Japanese patients with MMS compared with the 104 Japanese individuals from the 1000 Genomes Project. Disease genes associated with the arterial occlusive conditions represented by those of Rasopathies and PAH may provide novel diagnostic markers and future therapeutic targets for MMS as well as moyamoya disease with an unknown cause.