Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition: A Randomized Crossover Clinical Trial.

Importance: Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration. Objective: To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC. Design, Setting, and Participants: In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited. Interventions: After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise. Main Outcomes and Measures: The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC. Results: Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: -6.8 mL/kg/min; 95% CI, -10.7 to -2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: -37 Nm; 95% CI, -67 to -7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, -26.5 minutes/d; 95% CI, -42.0 to -11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing. Conclusions and Relevance: In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC. Trial Registration: ClinicalTrials.gov Identifier: NCT05445830.

Discordant gene expression in subcutaneous adipose and skeletal muscle tissues in response to exercise training.

Exercise has different effects on different tissues in the body, the sum of which may determine the response to exercise and the health benefits. In the present study, we aimed to investigate whether physical training regulates transcriptional network communites common to both skeletal muscle (SM) and subcutaneous adipose tissue (SAT). Eight such shared transcriptional communities were found in both tissues. Eighteen young overweight adults voluntarily participated in 7 weeks of combined strength and endurance training (five training sessions per week). Biopsies were taken from SM and SAT before and after training. Five of the network communities were regulated by training in SM but showed no change in SAT. One community involved in insulin- AMPK signaling and glucose utilization was upregulated in SM but downregulated in SAT. This diverging exercise regulation was confirmed in two independent studies and was also associated with BMI and diabetes in an independent cohort. Thus, the current finding is consistent with the differential responses of different tissues and suggests that body composition may influence the observed individual whole-body metabolic response to exercise training and help explain the observed attenuated whole-body insulin sensitivity after exercise training, even if it has significant effects on the exercising muscle.

Exertional breathlessness related to medical conditions in middle-aged people: the population-based SCAPIS study of more than 25,000 men and women.

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.

Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.

Emergence and Progression of Behavioral Motor Deficits and Skeletal Muscle Atrophy across the Adult Lifespan of the Rat.

The facultative loss of muscle mass and function during aging (sarcopenia) poses a serious threat to our independence and health. When activities of daily living are impaired (clinical phase), it appears that the processes leading to sarcopenia have been ongoing in humans for decades (preclinical phase). Here, we examined the natural history of sarcopenia in male outbred rats to compare the occurrence of motor behavioral deficits with the degree of muscle wasting and to explore the muscle-associated processes of the preclinical and clinical phases, respectively. Selected metrics were validated in female rats. We used the soleus muscle because of its long duty cycles and its importance in postural control. Results show that gait and coordination remain intact through middle age (40-60% of median lifespan) when muscle mass is largely preserved relative to body weight. However, the muscle shows numerous signs of remodeling with a shift in myofiber-type composition toward type I. As fiber-type prevalence shifted, fiber-type clustering also increased. The number of hybrid fibers, myofibers with central nuclei, and fibers expressing embryonic myosin increased from being barely detectable to a significant number (5-10%) at late middle age. In parallel, TGFß1, Smad3, FBXO32, and MuRF1 mRNAs increased. In early (25-month-old) and advanced (30-month-old) aging, gait and coordination deteriorate with the progressive loss of muscle mass. In late middle age and early aging due to type II atrophy (>50%) followed by type I atrophy (>50%), the number of myofibers did not correlate with this process. In advanced age, atrophy is accompanied by a decrease in SCs and ßCatenin mRNA, whereas several previously upregulated transcripts were downregulated. The re-expression of embryonic myosin in myofibers and the upregulation of mRNAs encoding the γ-subunit of the nicotinic acetylcholine receptor, the neuronal cell adhesion molecule, and myogenin that begins in late middle age suggest that one mechanism driving sarcopenia is the disruption of neuromuscular connectivity. We conclude that sarcopenia in rats, as in humans, has a long preclinical phase in which muscle undergoes extensive remodeling to maintain muscle mass and function. At later time points, these adaptive mechanisms fail, and sarcopenia becomes clinically manifest.

Bouts of rest and physical activity in C57BL/6J mice.

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 (rs>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.

Increased maximal oxygen uptake after sprint-interval training is mediated by central haemodynamic factors as determined by right heart catheterization.

There is a lack of knowledge regarding the contribution of central and peripheral factors to the increases in VO2max following sprint-interval training (SIT). This study investigated the importance of maximal cardiac output (Qmax ) in relation to VO2max improvements following SIT and the relative importance of the hypervolemic response on Qmax and VO2max . We also investigated whether systemic O2 extraction increased with SIT as has been previously suggested. Healthy men and women (n = 9) performed 6 weeks of SIT. State-of-the-art measurements: right heart catheterization, carbon monoxide rebreathing and respiratory gas exchange analysis were used to assess Qmax , arterial O2 content (ca O2 ), mixed venous O2 content (cv O2 ), blood volume (BV) and VO2max before and after the intervention. In order to assess the relative contribution of the hypervolemic response to the increases in VO2max , BV was re-established to pre-training levels by phlebotomy. Following the intervention, VO2max , BV and Qmax increased by 11% (P < 0.001), 5.4% (P = 0.013) and 8.8% (P = 0.004), respectively. cv O2 decreased by 12.4% (P = 0.011) and systemic O2 extraction increased by 4.0% (P = 0.009) during the same period, both variables were unaffected by phlebotomy (P = 0.589 and P = 0.548, respectively). After phlebotomy, VO2max and Qmax reverted back to pre-intervention values (P = 0.064 and P = 0.838, respectively) and were significantly lower compared with post-intervention (P = 0.016 and P = 0.018, respectively). The decline in VO2max after phlebotomy was linear to the amount of blood removed (P = 0.007, R = -0.82). The causal relationship between BV, Qmax and VO2max shows that the hypervolemic response is a key mediator of the increases in VO2max following SIT. KEY POINTS: Sprint-interval training (SIT) is an exercise model involving supramaximal bouts of exercise interspersed with periods of rest known for its efficiency in improving maximal oxygen uptake (VO2max ). In contrast to the commonly accepted view where central haemodynamic adaptations are considered to be the key mediators of increases in VO2max there have been propositions highlighting peripheral adaptations as the main mediators in the context of SIT-induced changes in VO2max . By combining right heart catheterization, carbon monoxide rebreathing and phlebotomy, this study shows that increases in maximal cardiac output due to the expansion of the total blood volume is a major explanatory factor for the improvement in VO2max following SIT, with a smaller contribution from improved systemic oxygen extraction. The present work not only clarifies a controversy in the field by using state-of-the-art methods, but also encourages future research to investigate regulatory mechanisms that could explain how SIT can lead to improvements in VO2max and maximal cardiac output similar to those that have previously been reported for traditional endurance exercise.

PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing.

Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases, represents an important goal in improving human health. Here, we show that the lipid synthesis enzyme phosphatidylethanolamine cytidyltransferase (PCYT2/ECT) is critical to muscle health. Human deficiency in PCYT2 causes a severe disease with failure to thrive and progressive weakness. pcyt2-mutant zebrafish and muscle-specific Pcyt2-knockout mice recapitulate the participant phenotypes, with failure to thrive, progressive muscle weakness and accelerated ageing. Mechanistically, muscle Pcyt2 deficiency affects cellular bioenergetics and membrane lipid bilayer structure and stability. PCYT2 activity declines in ageing muscles of mice and humans, and adeno-associated virus-based delivery of PCYT2 ameliorates muscle weakness in Pcyt2-knockout and old mice, offering a therapy for individuals with a rare disease and muscle ageing. Thus, PCYT2 plays a fundamental and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2-synthesized lipids to severe muscle dystrophy and ageing.

Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells.

Introduction: 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. Methods: 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. Results: 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. Discussion: 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.

Transcriptomic profiling reveals sex-specific molecular signatures of adipose endothelial cells under obesogenic conditions.

Female mice display greater adipose angiogenesis and maintain healthier adipose tissue than do males upon high-fat diet feeding. Through transcriptome analysis of endothelial cells (EC) from the white adipose tissue of male and female mice high-fat-fed for 7 weeks, we found that adipose EC exhibited pronouncedly sex-distinct transcriptomes. Genes upregulated in female adipose EC were associated with proliferation, oxidative phosphorylation, and chromatin remodeling contrasting the dominant enrichment for genes related to inflammation and a senescence-associated secretory of male EC. Similar sex-biased phenotypes of adipose EC were detectable in a dataset of aged EC. The highly proliferative phenotype of female EC was observed also in culture conditions. In turn, male EC displayed greater inflammatory potential than female EC in culture, based on basal and tumor necrosis factor alpha-stimulated patterns of gene expression. Our study provides insights into molecular programs that distinguish male and female EC responses to pathophysiological conditions.

Single-cell sequencing deconvolutes cellular responses to exercise in human skeletal muscle.

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.

Sphingomyelinase activity promotes atrophy and attenuates force in human muscle fibres and is elevated in heart failure patients.

BACKGROUND: Activation of sphingomyelinase (SMase) as a result of a general inflammatory response has been implicated as a mechanism underlying disease-related loss of skeletal muscle mass and function in several clinical conditions including heart failure. Here, for the first time, we characterize the effects of SMase activity on human muscle fibre contractile function and assess skeletal muscle SMase activity in heart failure patients. METHODS: The effects of SMase on force production and intracellular Ca2+ handling were investigated in single intact human muscle fibres. Additional mechanistic studies were performed in single mouse toe muscle fibres. RNA sequencing was performed in human muscle bundles exposed to SMase. Intramuscular SMase activity was measured from heart failure patients (n = 61, age 69 ± 0.8 years, NYHA III-IV, ejection fraction 25 ± 1.0%, peak VO2 14.4 ± 0.6 mL × kg × min) and healthy age-matched control subjects (n = 10, age 71 ± 2.2 years, ejection fraction 60 ± 1.2%, peak VO2 25.8 ± 1.1 mL × kg × min). SMase activity was related to circulatory factors known to be associated with progression and disease severity in heart failure. RESULTS: Sphingomyelinase reduced muscle fibre force production (-30%, P < 0.05) by impairing sarcoplasmic reticulum (SR) Ca2+ release (P < 0.05) and reducing myofibrillar Ca2+ sensitivity. In human muscle bundles exposed to SMase, RNA sequencing analysis revealed 180 and 291 genes as up-regulated and down-regulated, respectively, at a FDR of 1%. Gene-set enrichment analysis identified 'proteasome degradation' as an up-regulated pathway (average fold-change 1.1, P = 0.008), while the pathway 'cytoplasmic ribosomal proteins' (average fold-change 0.8, P < 0.0001) and factors involving proliferation of muscle cells (average fold-change 0.8, P = 0.0002) where identified as down-regulated. Intramuscular SMase activity was ~20% higher (P < 0.05) in human heart failure patients than in age-matched healthy controls and was positively correlated with markers of disease severity and progression, and with several circulating inflammatory proteins, including TNF-receptor 1 and 2. In a longitudinal cohort of heart failure patients (n = 6, mean follow-up time 2.5 ± 0.2 years), SMase activity was demonstrated to increase by 30% (P < 0.05) with duration of disease. CONCLUSIONS: The present findings implicate activation of skeletal muscle SMase as a mechanism underlying human heart failure-related loss of muscle mass and function. Moreover, our findings strengthen the idea that SMase activation may underpin disease-related loss of muscle mass and function in other clinical conditions, acting as a common patophysiological mechanism for the myopathy often reported in diseases associated with a systemic inflammatory response.

A HIF-1 signature dominates the attenuation in the human skeletal muscle transcriptional response to high-intensity interval training.

High-intensity interval training (HIIT) generates profound metabolic adaptations in skeletal muscle. These responses mirror performance improvements but follow a nonlinear pattern comprised of an initial fast phase followed by a gradual plateau effect. The complete time-dependent molecular sequelae that regulates this plateau effect remains unknown. We hypothesize that the plateau effect during HIIT is restricted to specific pathways with communal upstream transcriptional regulation. To investigate this, 11 healthy men performed nine sessions of HIIT [10 × 4 min of cycling at 91% of maximal heart rate (HRmax)] over a 3-wk period. Before and 3 h after the 1st and 9th exercise bout, skeletal muscle biopsies were obtained, and RNA sequencing was performed. Almost 2,000 genes across 84 pathways were differentially expressed in response to a single HIIT session. The overall transcriptional response to acute exercise was strikingly similar at 3 wk, 83% (n = 1,650) of the genes regulated after the 1st bout of exercise were similarly regulated by the 9th bout, albeit with a smaller effect size, and the response attenuated to on average 70% of the 1st bout. The attenuation differed substantially between pathways and was especially pronounced for glycolysis and cellular adhesion compared to, e.g., MAPK and vascular endothelial growth factor (VEGF)-A signaling. The attenuation was driven by a combination of changes in steady-state expression and specific transcriptional regulation. Given that the exercise intensity was progressively increased, and the attenuation was pathway-specific, we suggest that moderation of muscular adaptation after a period of training stems from targeted regulation rather than a diminished exercise stimulus.NEW & NOTEWORTHY This is the first study to address the phenomena of attenuation of the acute exercise response on a global genomic scale with a focus on underlying regulatory machinery and it is, to the best of our knowledge, the first study conducted in humans was exercise-induced regulation of different canonical pathways and transcription factors are contrasted with regards to attenuation after a period with regular exercise training. These results provide evidence for a pathway-specific regulated augmentation of the response to acute exercise over time that tracks with the successive adaptation on the systemic level.

Improvements in Maximal Oxygen Uptake After Sprint-Interval Training Coincide with Increases in Central Hemodynamic Factors.

INTRODUCTION: Sprint-interval training has been shown to improve maximal oxygen uptake, in part through peripheral muscle adaptations that increase oxygen utilization. In contrast, the adaptations of central hemodynamic factors in this context remain unexplored. PURPOSE: The aim of the current study was to explore the effects of sprint-interval training on maximal oxygen uptake and central hemodynamic factors. METHODS: Healthy men and women (n = 29; mean age, 27 ± 5 yr; height, 175 ± 8 cm; body mass, 72.5 ± 12.0 kg) performed 6 wk of sprint-interval training consisting of three weekly sessions of 10-min low-intensity cycling interspersed with 3 × 30-s all-out sprints. Maximal oxygen uptake, total blood volume, and maximal cardiac output were measured before and after the intervention. RESULTS: Maximal oxygen uptake increased by 10.3% (P < 0.001). Simultaneously, plasma volume, blood volume, total hemoglobin mass, and cardiac output increased by 8.1% (276 ± 234 mL; P < 0.001), 6.8% (382 ± 325 mL; P < 0.001), 5.7% (42 ± 41 g; P < 0.001), and 8.5% (1.0 ± 0.9 L·min-1; P < 0.001), respectively. Increased total hemoglobin mass along with measures of body surface area had a significant impact on the improvements in maximal oxygen uptake. CONCLUSIONS: Six weeks of sprint-interval training results in significant increases in hemoglobin mass, blood volume, and cardiac output. Because these changes were associated with marked improvements in maximal oxygen uptake, we conclude that central hemodynamic adaptations contribute to the improvement in maximal oxygen uptake during sprint-interval training.

Functional improvements to 6 months of physical activity are not related to changes in size or density of multiple lower-extremity muscles in mobility-limited older individuals.

Older adults are encouraged to engage in multicomponent physical activity, which includes aerobic and muscle-strengthening activities. The current work is an extension of the Vitality, Independence, and Vigor in the Elderly 2 (VIVE2) study - a 6-month multicenter, randomized, placebo-controlled trial of physical activity and nutritional supplementation in community dwelling 70-year-old seniors. Here, we examined whether the magnitude of changes in muscle size and quality differed between major lower-extremity muscle groups and related these changes to functional outcomes. We also examined whether daily vitamin-D-enriched protein supplementation could augment the response to structured physical activity. Forty-nine men and women (77 ± 5 yrs) performed brisk walking, muscle-strengthening exercises for the lower limbs, and balance training 3 times weekly for 6 months. Participants were randomized to daily intake of a nutritional supplement (20 g whey protein + 800 IU vitamin D), or a placebo. Muscle cross-sectional area (CSA) and radiological attenuation (RA) were assessed in 8 different muscle groups using single-slice CT scans of the hip, thigh, and calf at baseline and after the intervention. Walking speed and performance in the Short Physical Performance Battery (SPPB) were also measured. For both CSA and RA, there were muscle group × time interactions (P < 0.01). Significant increases in CSA were observed in 2 of the 8 muscles studied, namely the knee extensors (1.9%) and the hip adductors (2.8%). For RA, increases were observed in 4 of 8 muscle groups, namely the hip flexors (1.1 HU), hip adductors (0.9 HU), knee extensors (1.2 HU), and ankle dorsiflexors (0.8 HU). No additive effect of nutritional supplementation was observed. While walking speed (13%) and SPPB performance (38%) improved markedly, multivariate analysis showed that these changes were not associated with the changes in muscle CSA and RA after the intervention. We conclude that this type of multicomponent physical activity program results in significant improvements in physical function despite relatively small changes in muscle size and quality of some, but not all, of the measured lower extremity muscles involved in locomotion.

Substantial and Reproducible Individual Variability in Skeletal Muscle Outcomes in the Cross-Over Designed Planica Bed Rest Program.

To evaluate the individual responses in skeletal muscle outcomes following bed rest, data from three studies (21-day PlanHab; 10-day FemHab and LunHab) were combined. Subjects (n = 35) participated in three cross-over campaigns within each study: normoxic (NBR) and hypoxic bed rest (HBR), and hypoxic ambulation (HAMB; used as control). Individual variability (SDIR) was investigated as √(SD Exp 2 -SD Con 2 ), where SDExp and SDCon are the standard deviations of the change score (i.e., post - pre) in the experimental (NBR and HBR) and the control (HAMB) groups, respectively. Repeatability and moderators of the individual variability were explored. Significant SDIR was detected for knee extension torque, and thigh and calf muscle area, which translated into an individual response ranging from 3 to -17% for knee extension torque, -2 to -12% for calf muscle area, and -1 to -8% for thigh muscle area. Strong correlations were found for changes in NBR vs. HBR (i.e., repeatability) in thigh and calf muscle area (r = 0.65-0.75, P < 0.0001). Change-scores in knee extension torque, and thigh and calf muscle area strongly correlated with baseline values (P < 0.001; r between -0.5 and -0.9). Orthogonal partial least squares regression analysis explored if changes in the investigated variables could predict calf muscle area alterations. This analysis indicated that 43% of the variance in calf muscle area could be attributed to changes in all of the other variables. This is the first study using a validated methodology to report clinically relevant individual variability after bed rest in knee extension torque, calf muscle area, and (to a lower extent) thigh muscle area. Baseline values emerged as a moderator of the individual response, and a global bed rest signature served as a moderately strong predictor of the individual variation in calf muscle area alterations.

Interval-induced metabolic perturbation determines tissue fluid shifts into skeletal muscle.

Intense interval exercise has proven to be as effective as traditional endurance exercise in improving maximal oxygen uptake. Shared by these two exercise regimes is an acute reduction in plasma volume, which is a suggested stimulus behind exercise-induced increases in blood volume and maximal oxygen uptake. This study aimed to link exercise-induced metabolic perturbation with volume shifts into skeletal muscle tissue. Ten healthy subjects (mean age 33 ± 8 years, 5 males and 5 females) performed three 30 s all-out sprints on a cycle ergometer. Upon cessation of exercise magnetic resonance imaging, 31 Phosphorus magnetic resonance spectroscopy and blood samples were used to measure changes in muscle volume, intramuscular energy metabolites and plasma volume. Compared to pre-exercise, muscle volume increased from 1147.1 ± 35.6 ml to 1283.3 ± 11.0 ml 8 min post-exercise. At 30 min post-exercise, muscle volume was still higher than pre-exercise (1147.1 ± 35.6 vs. 1222.2 ± 6.8 ml). Plasma volume decreased by 16 ± 3% immediately post-exercise and recovered back to - 5 ± 6% after 30 min. Principal component analysis of exercise performance, muscle and plasma volume changes as well as changes in intramuscular energy metabolites showed generally strong correlations between metabolic and physiological variables. The strongest predictor for the volume shifts of muscle and plasma was the magnitude of glucose-6-phosphate accumulation post-exercise. Interval training leads to large metabolic and hemodynamic perturbations with accumulation of glucose-6-phosphate as a possible key event in the fluid flux between the vascular compartment and muscle tissue.

Major oscillations in spontaneous home-cage activity in C57BL/6 mice housed under constant conditions.

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.