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The mouse is the most important mammalian model in life science research and the behavior of the mouse is a key read-out of experimental interventions and genetic manipulations. To serve this purpose a solid understanding of the mouse normal behavior is a prerequisite. Using 14–19 months of cumulative 24/7 home-cage activity recorded with a non-intrusive technique, evidence is here provided for a highly significant circannual oscillation in spontaneous activity (1–2 SD of the mean, on average 65% higher during peak of highs than lows; P = 7E−50) of male and female C57BL/6 mice held under constant conditions. The periodicity of this hitherto not recognized oscillation is in the range of 2–4 months (average estimate was 97 days across cohorts of cages). It off-sets responses to environmental stimuli and co-varies with the feeding behavior but does not significantly alter the preference for being active during the dark hours. The absence of coordination of this rhythmicity between cages with mice or seasons of the year suggest that the oscillation of physical activity is generated by a free-running intrinsic oscillator devoid of external timer. Due to the magnitude of this rhythmic variation it may be a serious confounder in experiments on mice if left unrecognized.

The objective was to exploit the raw data output from a scalable home cage (type IIL IVC) monitoring (HCM) system (DVC®), to characterize pattern of undisrupted rest and physical activity (PA) of C57BL/6J mice. The system’s tracking algorithm show that mice in isolation spend 67% of the time in bouts of long rest (≥40s). Sixteen percent is physical activity (PA), split between local movements (6%) and locomotion (10%). Decomposition revealed that a day contains ˜7100 discrete bouts of short and long rest, local and locomotor movements. Mice travel ˜330m per day, mainly during the dark hours, while travelling speed is similar through the light-dark cycle. Locomotor bouts are usually <0.2m and <1% are >1m. Tracking revealed also fits of abnormal behaviour. The starting positions of the bouts showed no preference for the rear over the front of the cage floor, while there was a strong bias for the peripheral (75%) over the central floor area. The composition of bouts has a characteristic circadian pattern, however, intrusive husbandry routines increased bout fragmentation by ˜40%. Extracting electrode activations density (EAD) from the raw data yielded results close to those obtained with the tracking algorithm, with 81% of time in rest (<1 EAD s -1 ) and 19% in PA. Periods ≥40 s of file when no movement occurs and there is no EAD may correspond to periods of sleep (˜59% of file time). We confirm that EAD correlates closely with movement distance (r s >0.95) and the data agreed in ˜97% of the file time. Thus, albeit EAD being less informative it may serve as a proxy for PA and rest, enabling monitoring group housed mice. The data show that increasing density from one female to two males, and further to three male or female mice had the same effect size on EAD (˜2). In contrast, the EAD deviated significantly from this stepwise increase with 4 mice per cage, suggesting a crowdedness stress inducing sex specific adaptations. We conclude that informative metrics on rest and PA can be automatically extracted from the raw data flow in near-real time (< 1 hrs). As discussed, these metrics relay useful longitudinal information to those that use or care for the animals.

Abstract Context As many sports are divided in male/female categories, governing bodies have formed regulations on the eligibility for transgender individuals to compete in these categories. Yet, the magnitude of change in muscle mass and strength with gender-affirming treatment remains insufficiently explored. Objective This study explored the effects of gender-affirming treatment on muscle function, size, and composition during 12 months of therapy. Design, settings, participants In this single-center observational cohort study, untrained transgender women (TW, n = 11) and transgender men (TM, n = 12), approved to start gender-affirming medical interventions, underwent assessments at baseline, 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement, and 4 and 12 months after treatment initiation. Main outcome measures Knee extensor and flexor strength were assessed at all examination time points, and muscle size and radiological density (using magnetic resonance imaging and computed tomography) at baseline and 12 months after treatment initiation. Results Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps cross-sectional area (CSA) (15%) and radiological density (6%). In TW, the corresponding parameters decreased by –5% (muscle volume) and –4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained their strength levels. Conclusions One year of gender-affirming treatment resulted in robust increases in muscle mass and strength in TM, but modest changes in TW. These findings add new knowledge on the magnitude of changes in muscle function, size, and composition with cross-hormone therapy, which could be relevant when evaluating the transgender eligibility rules for athletic competitions.

BackgroundMultiple circulatory factors are increased in heart failure (HF). Many have been linked to cardiac and/or skeletal muscle tissue processes, which in turn might influence physical activity and/or capacity during HF. This study aimed to provide a better understanding of the mechanisms linking HF with the loss of peripheral function.Methods and resultsPhysical capacity measured by maximum oxygen uptake, myocardial function (measured by echocardiography), physical activity (measured by accelerometry), and mortality data was collected for patients with severe symptomatic heart failure an ejection fraction < 35% (n = 66) and controls (n = 28). Plasma circulatory factors were quantified using a multiplex immunoassay. Multivariate (orthogonal projections to latent structures discriminant analysis) and univariate analyses identified many factors that differed significantly between HF and control subjects, mainly involving biological functions related to cell growth and cell adhesion, extracellular matrix organization, angiogenesis, and inflammation. Then, using principal component analysis, links between circulatory factors and physical capacity, daily physical activity, and myocardial function were identified. A subset of ten biomarkers differentially expressed in patients with HF vs controls covaried with physical capacity, daily physical activity, and myocardial function; eight of these also carried prognostic value. These included established plasma biomarkers of HF, such as NT-proBNP and ST2 along with recently identified factors such as GDF15, IGFBP7, and TfR, as well as a new factor, galectin-4.ConclusionsThese findings reinforce the importance of systemic circulatory factors linked to hemodynamic stress responses and inflammation in the pathogenesis and progress of HF disease. They also support established biomarkers for HF and suggest new plausible markers.Graphic abstract

CD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in local tissues can result in significant exposure of cytotoxic T cells to the lactate metabolite. Lactate has been known to act as an immunosuppressor, at least in part due to its association with tissue acidosis. To dissect the role of the lactate anion, independently of pH, we performed phenotypical and metabolic assays, high-throughput RNA sequencing, and mass spectrometry, on primary cultures of murine or human CD8+ T cells exposed to high doses of pH-neutral sodium lactate. The lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and can displace glucose as a carbon source. Activation in the presence of sodium lactate significantly alters the CD8+ T cell transcriptome, including the expression key effector differentiation markers such as granzyme B and interferon-gamma. Our studies reveal novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells.

Physical activity is associated with reduced risk of several cancers, including aggressive prostate cancer. The mechanisms mediating the effects are not yet understood; among the candidates are modifications of endogenous hormone levels. Long-term exercise is known to reduce serum levels of growth stimulating hormones. In contrast, the endocrine effects of acute endurance exercise include increased levels of mitogenic factors such as GH and IGF-1. It can be speculated that the elevation of serum growth factors may be detrimental to prostate cancer progression into malignancy. The incentive of the current study is to evaluate the effect of acute exercise serum on prostate cancer cell growth. We designed an exercise intervention where 10 male individuals performed 60 minutes of bicycle exercise at increasing intensity. Serum samples were obtained before (rest serum) and after completed exercise (exercise serum). The established prostate cancer cell line LNCaP was exposed to exercise or rest serum. Exercise serum from 9 out of 10 individuals had a growth inhibitory effect on LNCaP cells. Incubation with pooled exercise serum resulted in a 31% inhibition of LNCaP growth and pre-incubation before subcutaneous injection into SCID mice caused a delay in tumor formation. Serum analyses indicated two possible candidates for the effect; increased levels of IGFBP-1 and reduced levels of EGF. In conclusion, despite the fear of possible detrimental effects of acute exercise serum on tumor cell growth, we show that even the short-term effects seem to add to the overall beneficial influence of exercise on neoplasia.

This study aimed to validate a fully automatic method to quantify knee-extensor muscle volume and exercise-induced hypertrophy. By using a magnetic resonance imaging-based fat-water separated two-point Dixon sequence, the agreement between automated and manual segmentation of a specific ~15-cm region (partial volume) of the quadriceps muscle was assessed. We then explored the sensitivity of the automated technique to detect changes in both complete and partial quadriceps volume in response to 8 weeks of resistance training in 26 healthy men and women. There was a very strong correlation (r = 0.98, P < 0.0001) between the manual and automated method for assessing partial quadriceps volume, yet the volume was 9.6% greater with automated compared with manual analysis (P < 0.0001, 95% limits of agreement −93.3 ± 137.8 cm 3 ). Partial muscle volume showed a 6.0 ± 5.0% (manual) and 4.8 ± 8.3% (automated) increase with training (P < 0.0001). Similarly, the complete quadriceps increased 5.1 ± 5.5% with training (P < 0.0001). The intramuscular fat proportion decreased (P < 0.001) from 4.1% to 3.9% after training. In conclusion, the automated method showed excellent correlation with manual segmentation and could detect clinically relevant magnitudes of exercise-induced muscle hypertrophy. This method could have broad application to accurately measure muscle mass in sports or to monitor clinical conditions associated with muscle wasting and fat infiltration.

Skeletal muscle adaptations to exercise have been associated with a range of health-related benefits, but cell type-specific adaptations within the muscle are incompletely understood. Here we use single-cell sequencing to determine the effects of exercise on cellular composition and cell type-specific processes in human skeletal muscle before and after intense exercise. Fifteen clusters originating from six different cell populations were identified. Most cell populations remained quantitatively stable after exercise, but a large transcriptional response was observed in mesenchymal, endothelial, and myogenic cells, suggesting that these cells are specifically involved in skeletal muscle remodeling. We found three subpopulations of myogenic cells characterized by different maturation stages based on the expression of markers such as PAX7 , MYOD1 , TNNI1 , and TNNI2 . Exercise accelerated the trajectory of myogenic progenitor cells towards maturation by increasing the transcriptional features of fast- and slow-twitch muscle fibers. The transcriptional regulation of these contractile elements upon differentiation was validated in vitro on primary myoblast cells. The cell type-specific adaptive mechanisms induced by exercise presented here contribute to the understanding of the skeletal muscle adaptations triggered by physical activity and may ultimately have implications for physiological and pathological processes affecting skeletal muscle, such as sarcopenia, cachexia, and glucose homeostasis. Single-cell RNA-sequencing of human skeletal muscle before and after exercise highlights how physical activity changes the composition and transcriptomic profile of muscle tissue.

Background The skeletal muscle hypothesis refers to a vicious cycle of successive deterioration of left ventricular function, skeletal muscle remodeling, and functional capacity in patients with heart failure. Despite extensive research, the regulatory mechanisms and their associations with clinical status and prognosis are still largely unclear. Methods To identify mechanisms and characterize underlying processes involved in the disease pathophysiology, we performed RNA sequencing and network analysis using human skeletal muscle samples from 58 patients with severe symptomatic heart failure. A co-expression network with communities involved in established biological processes within human skeletal muscle was identified and validated in two independent cohorts. Results Here, we show network communities associated with mitochondrial beta-oxidation, extracellular matrix remodeling, oxidative phosphorylation, and contractile elements with lower expression in heart failure patients than in age-matched controls. Based on the strong correlation with clinical features and prognosis, extracellular matrix remodeling, mitochondrial beta-oxidation, and p53 signalling communities are identified as key underlying processes. The former two communities are highly enriched with genes regulated by physical (in)activity, i.e., bed rest and exercise, and associated weakly with prognosis. Community related to p53 signalling, with CDKN1A as a key regulator, is increased in heart failure patients relative to age-matched controls and associated with worse prognosis. Conclusion The current work differentiates previously proposed factors underlying heart failure-induced skeletal muscle dysfunction, emphasizing the p53 signalling community and importance of biological age in this process. The distinct association with clinical status and prognosis furthermore supports pathophysiological significance and clinical potential of this community. Rullman et al. explore skeletal muscle gene-expression in patients with severe heart failure. They identify upregulation of p53 signaling, a process linked to aging and cell damage to be associated with mortality, highlighting the need to separate inactivity effects from disease-specific changes and cell-cycle control as a disease mechanism. Plain language summary Heart failure patients suffer from muscle weakness and reduced physical activity, symptoms that worsen with the disease progression. Although extensively studied, biological mechanisms behind it remain largely unclear. Here, we analysed skeletal muscle samples from patients with severe heart failure using gene-expression-based approach where transcripts with similar expression are grouped together into networks. We identified muscle processes related to energy metabolism and tissue repair to be altered in these patients, likely in part due to their physical inactivity. Importantly, we identified increased expression of genes linked to p53 signalling, process associated with aging and cell damage, which was also strongly related to patient outcomes. Our results distinguish and highlight the need to separate the negative effects of physical inactivity from disease-specific changes, which is essential for discovering new treatment targets.

Background Breathlessness is common in the population and can be related to a range of medical conditions. We aimed to evaluate the burden of breathlessness related to different medical conditions in a middle-aged population. Methods Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study of adults aged 50–64 years. Breathlessness (modified Medical Research Council [mMRC] ≥ 2) was evaluated in relation to self-reported symptoms, stress, depression; physician-diagnosed conditions; measured body mass index (BMI), spirometry, venous haemoglobin concentration, coronary artery calcification and stenosis [computer tomography (CT) angiography], and pulmonary emphysema (high-resolution CT). For each condition, the prevalence and breathlessness population attributable fraction (PAF) were calculated, overall and by sex, smoking history, and presence/absence of self-reported cardiorespiratory disease. Results We included 25,948 people aged 57.5 ± [SD] 4.4; 51% women; 37% former and 12% current smokers; 43% overweight (BMI 25.0–29.9), 21% obese (BMI ≥ 30); 25% with respiratory disease, 14% depression, 9% cardiac disease, and 3% anemia. Breathlessness was present in 3.7%. Medical conditions most strongly related to the breathlessness prevalence were (PAF 95%CI): overweight and obesity (59.6–66.0%), stress (31.6–76.8%), respiratory disease (20.1–37.1%), depression (17.1–26.6%), cardiac disease (6.3–12.7%), anemia (0.8–3.3%), and peripheral arterial disease (0.3–0.8%). Stress was the main factor in women and current smokers. Conclusion Breathlessness mainly relates to overweight/obesity and stress and to a lesser extent to comorbidities like respiratory, depressive, and cardiac disorders among middle-aged people in a high-income setting—supporting the importance of lifestyle interventions to reduce the burden of breathlessness in the population.