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Sepsis is associated with high rates of multiorgan failure and mortality. Altered mitochondrial function is an essential component of the early sepsis syndrome. However, its progression over time in peripheral blood mononuclear cells (PBMCs) is thus far unclear. Our purpose was to investigate this in the early phase of sepsis in ICU patients. A single-centre prospective observational cohort study was conducted in sepsis patients and compared with age- and sex-matched controls. Mitochondrial function was measured in PBMCs thrice during the first ICU week. RT-qPCR was used for semi-quantitative analysis of expression of genes involved in oxidative phosphorylation. Secondary endpoints included associations between mitochondrial function and (I) sepsis severity and (II) clinical outcomes, including 3-month mortality. Basal, ATP-linked, maximal and proton leak associated respiration were increased in sepsis patients (n = 25) compared to matched controls (n = 24) at all time points. This was associated with increased expression of SDBH (complex II) and ATP5F1A (complex V). Increased basal respiration was associated with 3-month mortality (HR 3.794, 95% CI 1.018–14.149, p  = 0.047). No differences were observed in other secondary outcomes. PBMC mitochondria were shown to have an increased respiratory rate during the first week of sepsis. Moreover, a progressive increase was negatively associated with 3-month survival.

Background Physical weakness is a key component of frailty, and is highly prevalent in older adults. While females have a higher prevalence and earlier onset, sex differences in the development of frailty-related physical weakness are hardly studied. Therefore, we investigated the intramuscular changes that differentiate between fit and weak older adults for each sex separately. Methods Male ( n  = 28) and female ( n  = 26) older adults (75 + years) were grouped on the basis of their ranks according to three frailty-related physical performance criteria. Muscle biopsies taken from vastus lateralis muscle were used for transcriptome and histological examination. Pairwise comparisons were made between the fittest and weakest groups for each sex separately, and potential sex-specific effects were assessed. Results Weak females were characterized by a higher expression of inflammatory pathways and infiltration of NOX2-expressing immune cells, concomitant with a higher VCAM1 expression. Weak males were characterized by a smaller diameter of type 2 (fast) myofibers and lower expression of PRKN . In addition, weakness-associated transcriptome changes in the muscle were distinct from aging, suggesting that the pathophysiology of frailty-associated physical weakness does not necessarily depend on aging. Conclusions We conclude that physical weakness-associated changes in muscle are sex-specific and recommend that sex differences are taken into account in research on frailty, as these differences may have a large impact on the development of (pharmaceutical) interventions against frailty. Trial registration number: The FITAAL study was registered in the Dutch Trial Register, with registration code NTR6124 on 14-11-2016 ( https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6124  ). Highlights • In female, but not male older adults, physical weakness was associated with a higher expression of intramuscular markers for inflammation. • In male, but not female older adults, physical weakness was associated with a smaller diameter of type 2 (fast) myofibers and lower PRKN expression. • Fit older adults (of both sexes) maintained expression levels comparable to young participants of weakness related genes, differing from frail participants.

Blood-based biomarkers allow monitoring of an individual’s health status and provide insights into metabolic and inflammatory processes in conditions like obesity, cardiovascular, and liver diseases. However, selecting suitable biomarkers and optimizing analytical assays presents challenges, is time-consuming and laborious. Moreover, knowledge of potential sex differences remains incomplete as research is often carried out in men. This study aims at enabling researchers to make informed choices on the type of biomarkers, analytical assays, and dilutions being used. More specifically, we analyzed plasma concentrations of >90 biomarkers using commonly available ELISA or electrochemiluminescence-based multiplex methods, comparing normal weight (BMI < 25; n = 40) with obese (BMI > 30; n = 40) adult blood donors of comparable age. To help choose optimal biomarker sets, we grouped frequently employed biomarkers into biological categories (e.g., adipokines, acute-phase proteins, complement factors, cytokines, myokines, iron metabolism, vascular inflammation), first comparing normal-weight with obese persons, and thereafter exploratively comparing women and men within each BMI group. Many biomarkers linked to chronic inflammation and dysmetabolism were elevated in persons with obesity, including several adipokines, interleukins, chemokines, acute-phase proteins, complement factors, and oxidized LDL. Further exploration suggests sex disparities in biomarker levels within both normal-weight and obese groups. This comprehensive dataset of biomarkers across diverse biological domains constitutes a reference resource that may provide valuable guidance for researchers in selecting appropriate biomarkers and analytical assays for own studies. Moreover, the dataset highlights the importance of taking possible sex differences into account.

Background Periods of muscle disuse occur during hospitalization, illness or the recovery from (sports) injury and lead to a rapid loss of muscle mass and the development of insulin resistance. Salbutamol is a fast‐acting β2‐adrenoreceptor agonist that may improve muscle protein synthesis and insulin sensitivity during experimental muscle disuse and thereby attenuate or preserve muscle mass; however, this has not yet been tested as a standalone intervention. Methods Effects of salbutamol treatment on muscle metabolism were studied in a randomized controlled trial using a human forearm immobilization model (n = 20). Before and after immobilization for 2 days, we measured whole‐body glucose disposal, forearm glucose uptake and amino acid kinetics during fasting and hyperinsulinaemic–hyperaminoacidaemic–euglycemic clamp conditions using forearm balance and L‐[ring‐2H5]‐phenylalanine infusion. Underlying mechanistic effects were studied as well using a complementary murine hindleg immobilization model (2 weeks) using tracer approaches (i.e., deuterated water and 14C‐labelled phenylalanine) and molecular analyses (e.g., RNA‐seq and western blot). Results In humans, salbutamol enhanced insulin‐stimulated glucose disposal on the whole‐body level (+21%, p = 0.010) but was unable to ameliorate the immobilization‐induced decrease in forearm glucose uptake. Salbutamol decreased the efflux of amino acids from the immobilized forearm, indicating increased muscle protein synthesis and/or inhibition of breakdown. However, this did not affect the immobilization‐induced impairment of amino acid net balance in both postabsorptive (−250%) and clamp conditions (−261%, both p = 0.031). In agreement, in mice, salbutamol increased cumulative muscle protein synthesis (+0.87%, p < 0.001) but did not result in a net gain of muscle mass upon immobilization due to an accompanying increase in muscle protein turnover (+13%, p < 0.001). Molecular analyses revealed immobilization inhibited salbutamol's effects on the muscle transcriptome, specifically the muscle contraction pathway (−2.1 normalized enrichment score, p < 0.001). Conclusions Salbutamol increases muscle mass and glucose uptake, although these effects are limited to active but not inactive muscles. This demonstrates that the mechanism of action and efficacy of β2‐adrenoreceptor signalling are hampered upon immobilization, which offers potential for a combined treatment intervention of reintroducing muscle contraction and salbutamol administration to improve muscle mass and clinical outcomes during episodes of physical inactivity.

Muscle-aging drives sarcopenia and is a major public health issue. Mice are frequently used as a model for human muscle-aging, however, research investigating their translational value is limited. In addition, mechanisms underlying muscle-aging may have sex-specific features in humans, but it is not yet assessed whether these are recapitulated in mice. Here, we studied the effects of aging on a functional, histological and transcriptional level at multiple timepoints in male and female mice (4, 17, 21 and 25 months), with particular emphasis on sex-differences. The effects of natural aging on the transcriptome of quadriceps muscle were compared to humans on pathway level. Significant loss of muscle mass occurred late, at 25 months, in both male (-17%, quadriceps) and female mice (-10%, quadriceps) compared to young control mice. Concomitantly, we found in female, but not male mice, a slower movement speed in the aged groups compared to the young mice (P < 0.001). Consistently, weighted gene co-expression network analysis revealed a stronger association between the aging-related reduction of movement and aging-related changes in muscle transcriptome of female compared to male mice (P < 0.001). In male, but not female mice, major distinctive aging-related changes occurred in the last age group (25 months), which highlights the necessity for careful selection of age using mice as a muscle-aging model. Furthermore, contrasting to humans, more aging-related changes were found in the muscle transcriptome of male mice compared to female mice (4090 vs. 2285 differentially expressed genes at 25 months, respectively). Subsequently, male mice recapitulated more muscle-aging related pathways characteristic for both male and female humans. In conclusion, our data show that sex has a critical effect on the mouse muscle-aging trajectory, although these do not necessarily reflect sex differences observed in the human muscle-aging trajectory.

An in silico target discovery pipeline was developed by including a directional and weighted molecular disease network for metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. This approach integrates text mining, network biology, and artificial intelligence/machine learning with clinical transcriptome data for optimal translational power. At the mechanistic level, the critical components influencing disease progression were identified from the disease network using in silico knockouts. The top-ranked genes were then subjected to a target efficacy analysis, following which the top-5 candidate targets were validated in vitro . Three targets, including EP300, were confirmed for their roles in liver fibrosis. EP300 gene-silencing was found to significantly reduce collagen by 37%; compound intervention studies performed in human primary hepatic stellate cells and the hepatic stellate cell line LX-2 showed significant inhibition of collagen to the extent of 81% compared to the TGFβ-stimulated control (1 μM inobrodib in LX-2 cells). The validated in silico pipeline presents a unique approach for the identification of human-disease-mechanism-relevant drug targets. The directionality of the network ensures adherence to physiologically relevant signaling cascades, while the inclusion of clinical data boosts its translational power and ensures identification of the most relevant disease pathways. In silico knockouts thus provide crucial molecular insights for successful target identification.

    Frailty is characterized by loss of physical function and is preferably diagnosed at an early stage (e.g., during pre-frailty). Unfortunately, sensitive tools that can aid early detection are lacking. Blood-based biomarkers, reflecting pathophysiological adaptations before physical symptoms become apparent, could be such tools. We identified candidate biomarkers using a mechanism-based computational approach which integrates a priori defined database-derived clinical biomarkers and skeletal muscle transcriptome data. Identified candidate biomarkers were used as input for a sex-specific correlation analysis, using individual gene expression data from female ( n  = 24) and male ( n  = 28) older adults (all 75 + years, ranging from fit to pre-frail) and three frailty-related physical parameters. Male and female groups were matched based on age, BMI, and Fried frailty index. The best correlating candidate biomarkers were evaluated, and selected biomarkers were measured in serum. In females, myostatin and galectin-1 and, in males, cathepsin B and thrombospondin-4 serum levels were significantly different between the physically weakest and fittest participants (all p  < 0.05). Logistic regression confirmed the added value of these biomarkers in conjunction with age and BMI to predict whether the subjects belonged to the weaker or fittest group (AUC = 0.80 in females and AUC = 0.83 in males). In conclusion, both in silico and in vivo analyses revealed the sex-specificity of candidate biomarkers, and we identified a selection of potential biomarkers which could be used in a biomarker panel for early detection of frailty. Further investigation is needed to confirm these leads for early detection of frailty.

Sex differences in muscle aging are poorly understood, but could be crucial for the optimization of sarcopenia-related interventions. To gain insight into potential sex differences in muscle aging, we recruited young (23 ± 2 years, 13 males and 13 females) and old (80 ± 3.5 years, 28 males and 26 females) participants. Males and females in both groups were highly matched, and vastus lateralis muscle parameters of old versus young participants were compared for each sex separately, focusing on gene expression. The overall gene expression profiles separated the sexes, but similar gene expression patterns separated old from young participants in males and females. Genes were indeed regulated in the same direction in both sexes during aging; however, the magnitude of differential expression was sex specific. In males, oxidative phosphorylation was the top-ranked differentially expressed process, and in females, this was cell growth mediated by AKT signaling. Findings from RNA-seq data were studied in greater detail using alternative approaches. In addition, we confirmed our data using publicly available data from three independent human studies. In conclusion, top-ranked pathways differ between males and females, but were present and altered in the same direction in both sexes. We conclude that the same processes are associated with skeletal muscle aging in males and females, but the differential expression of those processes in old vs. young participants is sex specific.

Electrical pulse stimulation (EPS) of skeletal muscle cells is increasingly used to model exercise In vitro. The murine C2C12 myotube system has become a common platform for such studies, yet wide variability in EPS protocols hampers reproducibility and cross‐study comparisons. In this technical review, we analysed 54 peer‐reviewed studies that employed EPS in C2C12 and extracted used EPS protocols to provide an overview of the most commonly used settings for the EPS parameters (pulse duration, frequency, voltage and stimulation duration). Additionally, we summarized the biological processes investigated in these studies to illustrate the range of research topics typically addressed using this model. The majority of studies used 2 ms pulses at 1 Hz and moderate voltages (10–20 V), often over 24 h of stimulation. Glucose uptake was the most commonly assessed endpoint, followed by AMPK activation, inflammation and mitochondrial adaptations. Correlation analyses revealed interdependence between pulse duration, voltage and EPS duration, indicating that these parameters are often balanced to avoid excessive or suboptimal stimulation. While frequency was largely standardized, voltage and pulse duration showed greater variation. Our findings underscore the need for more detailed parameter reporting and deliberate protocol design aligned with specific experimental objectives, such as mimicking endurance‐ or resistance‐type exercise stimuli. This review serves as a resource for selecting EPS parameters tailored to specific biological processes and encourages standardization to improve translational relevance. What is the central question of this study? In electrical pulse stimulation (EPS) protocols in C2C12 myotubes, What are the commonly used parameters, experimental approaches, and reported biological outcomes in C2C12 myotube electrical pulse stimulation (EPS) protocols aimed at modeling skeletal muscle contraction and exercise physiology? What is the main finding and its importance? Analysis of 54 studies revealed common EPS settings (2 ms pulse, 1 Hz, 20 V, 24 h). A higher voltage was associated with a longer length of stimulation, but a lower total duration of EPS. Protocols varied depending on the purpose of the research. This review offers a valuable guide for protocol selection and promotes standardization across future EPS studies.

A digital-first strategy is increasingly implemented to reduce participant burden, accelerate recruitment, collect real-world data, and increase the diversity of the study population. However, fully remote studies lack face-to-face interaction, which may affect motivation, particularly in the delivery of personalized nutritional advice. Additionally, self-reported data may vary in terms of standardization and completeness. The study's primary objective is to evaluate the feasibility of conducting a fully remote, fully digital randomized controlled nutritional intervention, including participant experience and the capability to perform do-it-yourself anthropometric measurements at home. Secondary objectives are to determine whether self-collected data could detect changes in body weight and other anthropometric outcomes, and to compare the effectiveness of generic versus personalized nutrition advice, with and without personalized food boxes. We conducted a fully online, 3-arm randomized controlled trial including adults with overweight or obesity who were motivated to lose weight. Participants were assigned to a control group that received generic advice (n=43), a personalized intervention group that received personalized advice only (n=40), or a personalized intervention plus group that received personalized advice plus personalized food boxes (n=39). The 6-week intervention was delivered entirely digitally, and all anthropometric measurements, questionnaires, and dietary data were self-collected at home. Feasibility was assessed using adherence metrics, completion of self-measurements, and a user-experience questionnaire. Secondary analyses evaluated weight loss, changes in anthropometry, and exploratory associations, including sex differences. Feasibility was high-102 out of 122 (83.6%) participants found the self-measured anthropometric assessments easy to perform, and 112 (91.8%) participants reported that completing questionnaires from home was easy. For secondary outcomes, participants receiving personalized, but not generic, nutritional advice significantly lost body weight (-1.0 kg; P=.002). Participants receiving personalized food boxes in addition to personalized nutritional advice lost significantly more body weight than the other 2 groups (-2.5 kg; P=.001) and also showed a decrease in hip circumference (-2.9 cm; P=.01). Personalized advice was not easier or more enjoyable to implement than generic nutritional advice, whereas the addition of personalized food boxes improved the ease of implementing personalized nutritional advice (P<.001). All participants, irrespective of the intervention arm, reduced intake of unhealthy food groups, including ready-made meals (113.6 g vs 78.5 g, -30.9%); sauces and gravy (18.8 g vs 10.0 g, -46.8%); sweet snacks (84.8 g vs 64.1 g, -24.4%); savory snacks (50.5 g vs 40.0 g, -20.1%); bread, pasta, rice, and wraps (nutritional quality score of 1.9 vs 1.7, -10.5%); and vegetables (129.0 g vs 118.7 g, -8.0%); and replaced coffee with tea. This study demonstrates that fully remote, participant-led nutritional intervention studies are feasible, with participants able to independently perform anthropometric measurements and self-report data of sufficient quality to detect meaningful effects. Personalized nutritional advice resulted in greater weight loss than generic advice, and the addition of personalized food boxes further enhanced the beneficial anthropometric effects of the intervention. We conclude that such nutritional intervention studies can be conducted fully online, resulting in measurable anthropometric effects after 6 weeks. ClinicalTrials.gov NCT06547983; https://clinicaltrials.gov/ct2/show/NCT06547983.