Disuse muscle atrophy (DMA) is a significant healthcare challenge characterized by progressive loss of muscle mass and function resulting from prolonged inactivity. The development of effective strategies for muscle recovery is essential. In this study, we established a DMA mouse model through hindlimb suspension to evaluate the therapeutic potential of lactate in alleviating the detrimental effects on the gastrocnemius muscle. Using NMR-based metabolomic analysis, we investigated the metabolic changes in DMA-injured gastrocnemius muscles compared to controls and evaluated the beneficial effects of lactate treatment. Our results show that lactate significantly reduced muscle mass loss and improved muscle function by downregulating Murf1 expression, decreasing protein ubiquitination and hydrolysis, and increasing myosin heavy chain levels. Crucially, lactate corrected perturbations in four key metabolic pathways in the DMA gastrocnemius: the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; histidine metabolism; and arginine and proline metabolism. In addition to phenylalanine-related pathways, lactate also plays a role in regulating branched-chain amino acid metabolism and energy metabolism. Notably, lactate treatment normalized the levels of eight essential metabolites in DMA mice, underscoring its potential as a therapeutic agent against the consequences of prolonged inactivity and muscle wasting. This study not only advances our understanding of the therapeutic benefits of lactate but also provides a foundation for novel treatment approaches aimed at metabolic restoration and muscle recovery in conditions of muscle wasting.

Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy.
We performed a genome-wide association analysis in the Women\'s Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated.
The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

UNASSIGNED: Preeclampsia (PE) mainly occurs in pregnant women and is hereditary. Several genome-wide association studies (GWAS) on Caucasian samples have reported some gene loci that are associated with preeclampsia. However, these studies have not reached consistent conclusions. No previous GWAS has examined preeclampsia in the Chinese Han population.
UNASSIGNED: This study aimed to identify common genetic variations associated with preeclampsia in the Chinese Han population through two-stage case‒control studies. The discovery cohort included 92 patients with severe preeclampsia and 187 healthy controls. The validation cohort included 52 patients with preeclampsia and 104 controls. A genome-wide association study was performed to identify putative preeclampsia genes in the discovery cohort, with validation in the validation cohort.
UNASSIGNED: In the discovery cohort, GWAS demonstrated that 19 single-nucleotide polymorphisms (SNPs) were associated with preeclampsia (P < 10-5). The pathway analysis revealed that these 19 SNP representative genes were mainly enriched in the adenylyl cyclase-inhibiting G-protein coupled receptor signaling pathway. After validation in the validation cohort, rs13176432 and rs13210237 remained closely related to preeclampsia (P<0.05). In the combined data set, the frequency of the G allele in rs13176432 was significantly higher in cases with preeclampsia than in controls (P = 5 × 10-6). The frequency of the A allele in rs13210237 was higher in the preeclampsia group (P = 8 × 10-6). The rs13210237 representative genes include HSF2 and GJA1, while the rs13176432 representative gene is TRIM36. There were no differences in genotype distribution between the early-onset and late-onset preeclampsia groups (P > 0.05). Furthermore, rs13210237 and rs13176432 were related to preeclampsia in the adjusted regression model (P < 0.000).
UNASSIGNED: In this study of two independent cohorts, we found that rs13210237 and rs13176432 might be novel preeclampsia-susceptible genetic factors in the Han population in China. However, there was no association between the onset of preeclampsia and these genotypes.

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient\'s sensitivity to therapeutic alkylating agents.

BACKGROUND: The early diagnosis of sepsis is beneficial to put forward a reasonable clinical treatment plan as soon as possible. This study was to explore the expression of Tripartite Motif 7 (TRIM7) in peripheral blood mononuclear cells (PBMCs) of patients with sepsis and its diagnostic value.
METHODS: This is a cross-sectional study. A total of 69 patients with infectious diseases were enrolled in the emergency room. They were divided into the sepsis group (34 cases) and the non-sepsis infection group (35 cases). There were 25 healthy subjects who were selected as the control group. The expression of TRIM7 in PBMCs was observed by immunofluorescence staining. The correlation between the expression of TRIM7 mRNA and acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, white blood cell (WBC), C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor (TNF)-α and interleukin (IL)-6 was discussed. The receiver operating characteristic (ROC) curve was utilized for evaluating the value of TRIM7 expression for the early diagnosis of sepsis.
RESULTS: The fluorescence intensity representing the expression level of TRIM7 in PBMCs of patients in the sepsis group was the lowest among three groups. The TRIM7 mRNA expression in PBMCs of the sepsis group was greatly decreased in comparison with that of the non-sepsis infection group and control group (P < 0.05). Spearman correlation analysis indicated that TRIM7 mRNA expression was negatively correlated with APACHE II score, SOFA score, WBC, CRP, PCT, TNF-α and IL-6. ROC curve analysis revealed that the area under curve (AUC) of TRIM7 mRNA expression in PBMCs for the diagnosis of sepsis was 0.798, with a 95% confidence interval of 0.691- 0.905, a sensitivity of 73.5%, and a specificity of 77.1%.
CONCLUSIONS: The expression of TRIM7 in PBMCs of patients with sepsis is significantly down-regulated, which has certain clinical value for early diagnosis of sepsis.

This study aimed to evaluate the impact of a 12-week calorie-restricted diet and recreational sports training on gene expressions IL-15, ATROGIN-1 and MURF-1 in skeletal muscle of T2D patients.
Older adults with T2D (n = 39, 60 ± 6.0 years, BMI 33.5 ± 0.6 kg/m2) were randomly allocated to Diet+Soccer (DS), Diet+Running (DR) or Diet (D). The training sessions were moderate-to-high-intensity and performed 3 × 40 min/week for 12-weeks. Gene expression from vastus lateralis muscle obtained by qRT-PCR, dual-energy X-ray and fasting blood testing measurements were performed before and after 12-weeks. Statistical analysis adopted were two-way ANOVA and Paired t-test for gene expression, and RM-ANOVA test for the remainder variables.
Total body weight was reduced in ~4 kg representing body fat mass in all groups after 12-weeks (P < 0.05). HbA1c values decreased in all groups post-intervention. Lipids profile improved in the training groups (P < 0.05) after 12-weeks. ATROGIN-1 and MURF-1 mRNA reduced in the DS (1.084 ± 0.14 vs. 0.754 ± 1.14 and 1.175 ± 0.34 vs. 0.693 ± 0.12, respectively; P < 0.05), while IL-15 mRNA increased in the DR (1.056 ± 0.12 vs. 1.308 ± 0.13; P < 0.05) after 12-weeks intervention.
Recreational training with a moderate calorie-restricted diet can downregulates the expression of atrophy-associated myokines and increases the expression of anti-inflammatory gene IL-15.

Disruption of age-related processes seems to play a relevant role in health effects related to night shift (NS) work. We aim to verify whether NS work can influence biological age (BA), estimated through Zbieć-Piekarska\'s epigenetic signature, based on methylation of five CpG sites in ELOVL2, C1orf132/MIR29B2C, TRIM59, KLF14, and FHL2. Forty-six female nurses working in NS were matched by age and length of employment with 51 female colleagues not working in NS. Each subject filled in a questionnaire (including the Effort Reward Imbalance (ERI) index to assess job stress) and gave a blood sample. Age acceleration (AA) was estimated by regressing BA on chronological age and taking the residuals. Multivariate linear regression models were applied. BA was not associated with NS. However, we did observe an increase in AA per each year in NS in subjects with overweight/obesity (β = 0.46, 95% CI: 0.05; 0.87, p = 0.03), experiencing work-related stress (β = 0.58, 95% CI: 0.10; 1.06, p = 0.018), or both (β = 0.66, 95% CI: 0.03; 1.29, p = 0.041). Although based on a small sample size, our findings suggest an increased BA only among hypersusceptible subjects and is worth further investigation, also in light of recent results suggesting a higher breast cancer risk in women with increased AA.

Resistance exercise transiently activates anabolic and catabolic systems in skeletal muscle. Leucine-enriched essential amino acids (LEAAs) are reported to stimulate the muscle anabolic response at a lower dose than whey protein. However, little is known regarding the effect of LEAA supplementation on the resistance exercise-induced responses of the anabolic and catabolic systems. Here, we conducted a randomized, double-blind, placebo-controlled, parallel-group comparison trial to investigate the effect of LEAA supplementation on mechanistic target of rapamycin complex 1 (mTORC1), the ubiquitin-proteasome system and inflammatory cytokines after a single bout of resistance exercise in young men. A total of 20 healthy young male subjects were supplemented with either 5 g of LEAA or placebo, and then they performed 10 reps in three sets of leg extensions and leg curls (70% one-repetition maximum). LEAA supplementation augmented the phosphorylation of mTORSer2448 (+77.1%, p < 0.05), p70S6KThr389 (+1067.4%, p < 0.05), rpS6Ser240/244 (+171.3%, p < 0.05) and 4EBP1Thr37/46 (+33.4%, p < 0.05) after resistance exercise. However, LEAA supplementation did not change the response of the ubiquitinated proteins, MuRF-1 and Atrogin-1 expression. Additionally, the mRNA expression of IL-1β and IL-6 did not change. These data indicated that LEAA supplementation augments the effect of resistance exercise by enhancing mTORC1 signal activation after exercise.

Muscle mass is known to rapidly decrease with muscle disuse. Previous reports suggest that repetitive blood flow restriction (BFR) mitigates the reduction of muscle mass with disuse. However, the effects of BFR on muscle atrophy and gene expression levels in muscle during cast immobilization have not been clarified.
To investigate the effect of BFR on muscle atrophy and gene expression levels during cast immobilization in humans, we recruited 10 healthy males who were randomly divided into the control and BFR treatment groups. All subjects were immobilized with a cast for 14 days. BFR treatment was conducted only in the BFR group. We evaluated cross sectional area (CSA) of thigh muscles by magnetic resonance imaging before and 14 days after cast immobilization. A percutaneous biopsy of the vastus lateralis muscle (VL) was performed before and 1, 7, and 14 days after cast immobilization. Expression of genes related to muscle atrophy and synthesis were evaluated using real-time PCR.
The CSA of the VL and the thigh flexor muscles were significantly decreased in both groups; however, percent decrease in CSA was significantly smaller in the BFR group compared with the control group. In two-way repeated ANOVA analysis, the time × treatment interaction in gene expression of the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) was significant, and elevated MURF1 expression level by cast immobilization was seemed to be suppressed by the BFR treatment.
BFR treatment may prevent reduced VL and thigh flexor muscles and increased MuRF1 expression level during cast immobilization. Further study is required to confirm these results.

LGMD D2 is a disease caused by TNPO3 mutation. We describe the expression of TNPO3 and selected proteins, likely modified by TNPO3 mutation, in muscle biopsies of affected patients. We also aim to find other genes involved in pathways correlated to TNPO3. Our morphological study on LGMD D2 muscle described the expression of TNPO3 and SRSF1, a splicing factor transported by TNPO3. Moreover, we investigated some sarcomeric and nuclear proteins, likely altered by TNPO3 mutation. Through an in silico approach we tried to identify genes involved in pathways that include, besides TNPO3 and SRSF1, p62 and Murf-1, altered in LGMD D2. In patients\' muscles TNPO3 appeared weaker and randomly organized, with sporadic cytoplasmic aggregates positive for TNPO3; both SRSF1 and sarcomeric alpha actinin showed a different expression, while there were no alterations in the expression of the nuclear proteins. The in silico study lead to identify five genes, all coding for proteins responsible for muscle contraction. Our data suggest a possible interference in the morphology and function of myofibrillar network by mutated TNPO3; these findings are supported by the in silico identification of genes involved in muscle contraction that could help to explain the pathogenic mechanisms of LGMD D2.