Mutations in the desmin gene cause skeletal myopathies and cardiomyopathies. The objective of this study was to elucidate the molecular pathology induced by the expression of R405W mutant desmin in murine skeletal muscle.
A comprehensive characterization of the skeletal muscle pathology in hetero- and homozygous R405W desmin knock-in mice was performed. This included grip strength, blood acylcarnitine and amino acid, histological, ultrastructural, immunofluorescence, immunoblot, ribosomal stalling, RNA sequencing and proteomic analyses.
Both hetero- and homozygous R405W desmin knock-in mice showed classical myopathological features of a myofibrillar myopathy with desmin-positive protein aggregation, degenerative changes of the myofibrillar apparatus and mitochondrial alterations. Muscle weakness and increased blood concentrations of acylcarnitines and amino acids were only present in homozygous animals. During its translation, mutant desmin did not induce terminal ribosomal stalling. Analyses of RNA sequencing and proteomic data from soleus muscle of 3-month-old mice depicted 59 up- and 3 down-regulated mRNAs and 101 up- and 18 down-regulated proteins that were shared between the heterozygous and homozygous genotypes in the respective omics datasets compared to the wild-type genotype. Combined analysis of the omics data demonstrated 187 significantly dysregulated candidates distributed across four groups of regulation. A down-regulation on the mRNA and protein levels was observed for a multitude of mitochondrial proteins including essential proton gradient-dependent carriers. Up-regulation on both omics levels was present for the transcription factor Mlf1, which is a binding partner of protein quality control related Dnajb6. Down-regulated on mRNA but up-regulated on the protein level was the sarcomeric lesion marker Xirp2 (xin actin-binding repeat-containing protein 2), whereas Ces2c (acylcarnitine hydrolase) was regulated in the opposite way.
The present study demonstrates that the expression of mutant desmin results in a myofibrillar myopathy in hetero- and homozygous R405W desmin knock-in mice. Combined morphological, transcriptomic and proteomic analyses helped decipher the complex pattern of early pathological changes induced by the expression of mutant desmin. Our findings highlight the importance of major mitochondrial alterations, including essential proton gra
Gastric cancer (GC) patients often have nutritional risks or malnutrition, and neoadjuvant chemotherapy (NAC) tends to exacerbate malnutrition. Body composition parameters are associated with the prognosis of GC patients. Little is known about body composition changes during NAC and its role in clinical outcomes.
This was a secondary analysis of a Phase 3, open-label, multicentre, randomized clinical trial (RCT) (NCT01364376), assessing the usefulness, safety and efficacy of S-1 plus oxaliplatin (SOX) vs. fluorouracil, leucovorin and oxaliplatin (FOLFOX) as a perioperative chemotherapy regimen for patients with locally advanced GC. Pre-NAC and post-NAC computer tomography (CT) were collected to evaluate the prognostic role of skeletal muscle, adipose tissue and their dynamic change. Overall survival (OS) and progression-free survival (PFS) rates were calculated using the Kaplan–Meier method.
A total of 583 patients from 12 Chinese hospitals were enrolled. After exclusion, 423 patients who proceeded to surgery were used for further analysis. The median age was 60 (IQR: 54, 66) years, and 133 patients (31.4%) were female. Prior to NAC, 132 (31.2%) patients were diagnosed with sarcopenia. There was no significant difference in overall survival between sarcopenia and non-sarcopenia patients (p = 0.363). During NAC, most patients suffered skeletal muscle (SM) loss (n = 268, 63.4%), subcutaneous adipose tissue (SAT) loss (n = 236, 55.8%) and visceral adipose tissue (VAT) loss (n = 254, 60.0%). Patients with SAT loss > 12.5% had significantly worse PFS (p = 0.005) and OS (p = 0.003) than those without. Patients with VAT loss > 15% had significantly worse PFS (p = 0.003) and OS (p = 0.004) than the stable or gain group. Patients with SMI loss > 4.7% had significantly worse PFS (p = 0.043) and showed a tendency of reduced OS (p = 0.181) than those without. In patients without sarcopenia, the incidence of grade 3/4 neutropenia in the FOLFOX group was higher than that of the SOX group (p = 0.019). In patients with myosteatosis, the incidence of Grade 3/4 thrombocytopenia in the SOX group was higher than that of the FOLFOX group (p < 0.001).
In this RCT study, patients with GC experience significant losses of muscle and adipose tissue during NAC. A high level of adipose tissue or muscle l
Sarcopenia, a significant geriatric syndrome, faces challenges in accurate diagnosis due to limitations of current imaging techniques. This study explores the novel application of multispectral optoacoustic tomography (MSOT) in evaluating sarcopenia, focusing on quantifying oxygen dynamics and collagen distribution in skeletal muscles.
We conducted MSOT imaging on the lower limbs of senescence-accelerated mouse prone 8 (SAMP8; n = 14) and senescence-accelerated mouse resistant 1 (SAMR1; n = 8) models, using light wavelengths of 760, 840 and 930 nm. CT, histopathology and immunofluorescence were used for cross-validation.
Label-free MSOT imaging directly visualized muscle structure and metabolism with high spatiotemporal resolution. Compared to SAMR1 controls, sarcopenic SAMP8 mice demonstrated 23.8% lower HbO2 levels (SAMP8: 0.0016 ± 0.0003 a.u. vs. SAMR1: 0.0021 ± 0.0005 a.u.; p = 0.018) and reduced metabolic activity in skeletal muscles. SAMP8 mice also revealed 43.2% higher collagen content (SAMP8: 3.451 ± 1.159 a.u. vs. SAMR1: 2.409 ± 0.635 a.u.; p = 0.030) alongside more disordered muscle structure, suggesting increased fibrosis. An inverse correlation was observed between computed tomography (CT) values and MSOT-derived collagen signals (r = −0.789, p < 0.001), whereas no such correlation existed with HbO2, indicating that MSOT provides unique metabolic insights beyond traditional imaging techniques.
This first application of MSOT in sarcopenia research highlights its potential as a noninvasive, real-time tool for early diagnosis, therapeutic evaluation and mechanistic understanding. Its ability to detect metabolic changes not captured by CT underscores its complementary role in comprehensive muscle assessment. Future research should focus on longitudinal studies and clinical translation.
Muscular fitness, particularly handgrip strength, is increasingly recognized as a robust marker of cardiometabolic risk (CMR) in children and adolescents. However, evidence-based diagnostic thresholds for identifying at-risk individuals remain scarce, particularly in children. This study aimed to (1) establish sex-specific diagnostic thresholds for handgrip strength normalized to body weight to identify elevated CMR in children aged 8–11 years, and (2) synthesize existing evidence through a systematic review and meta-analysis across pediatric age groups, integrating the new data with existing evidence.
We analyzed cross-sectional data from 1124 Spanish children (49.7% girls) aged 8–11 years participating in the MOVI-2 study. Normalized handgrip strength was associated with a CMR index composed of waist circumference, triglyceride-to-HDL ratio, mean arterial pressure and fasting insulin. Diagnostic accuracy was assessed using receiver operating characteristic curves and optimized with the Youden Index. Results from the MOVI-2 study and other diagnostic accuracy studies were combined in a meta-analysis for identifying the optimal threshold for normalized handgrip strength to identify elevated CMR in youth.
In the MOVI-2 study, thresholds were 0.38 for boys and 0.34 for girls, with area under the curve (AUC) of 0.77 (95% CI: 0.73–0.81) and 0.75 (95% CI: 0.70–0.79), respectively. The systematic review and meta-analysis followed PRISMA-DTA guidelines and included nine additional studies (n = 10 588). Meta-analytic thresholds for normalized handgrip strength were 0.30 for girls and 0.39 for boys in childhood (6–12 years), and 0.36 for girls and 0.42 for boys in adolescence (13–18 years), with the highest diagnostic accuracy observed in adolescent girls (AUC = 0.80, 95% CI: 0.77–0.83; Youden Index = 0.60). Children showed greater heterogeneity, particularly in specificity.
Despite certain limitations, our findings provide clinically relevant, sex- and age-specific thresholds for normalized handgrip strength to identify elevated CMR in youth. These thresholds may serve as a valuable starting point for CMR screening in both boys and girls.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：