No immediate change in systemic cytokines following an eccentric muscle training session in people with multiple sclerosis.

Background: Eccentric muscle contractions elicit distinct physiological responses, including modulation of the cytokine profile. Although relevant for rehabilitation, the effect of eccentric muscle training on the immune system has never been investigated in multiple sclerosis (MS). Objectives: Examine the immediate cytokine response of interleukin-4 (IL-4), IL-6, IL-10, IL-17a, interferon-gamma, and tumor necrosis factor-alpha after a moderate eccentric training session in individuals with MS. Additionally, further investigate the association between systemic cytokine levels at rest and clinical measures of mobility and lower limb functional strength. Design: Observational study. Methods: The first session included blood sampling for baseline cytokine measures. Subsequently, the participant completed a battery of clinical assessments related to mobility and lower limb strength, that is, the Timed-Up-and-Go Test, Five-Repetition-Sit-to-Stand-Test (5STS), Four-Square-Step-Test, and Two-Minute-Walk-Test. The second session included the eccentric exercise training session, followed by a second blood sampling to assess the acute cytokine response to the eccentric training bout. This session comprised 10 exercises concentrating on the strength of the trunk and lower extremities. Results: Twenty-seven people with MS (pwMS), with a mean age of 40.1 years, participated in the study. No difference was demonstrated in the cytokine concentration values between baseline and immediately after the eccentric training session. The 5STS explained 30.3% of the variance associated with interferon-gamma, 14.8% with IL-4, and 13.8% with IL-10. Conclusion: An eccentric training bout does not impact cytokine concentration in the blood and, consequently, does not boost a pro-inflammatory response, thus, it can be performed on pwMS in a rehabilitation setting.

A strength-lengthening exercise session doesn't affect inflammation markers in people with multiple sclerosis The article explores how a specific type of exercise, called eccentric muscle training, affects people with multiple sclerosis (MS). Eccentric muscle training involves exercises where the muscle lengthens under tension, like when you slowly lower a heavy object. This type of exercise is known for causing unique physical responses, including changes in certain proteins in the blood that help control the immune system and inflammation. The main goal of the study was to see if a session of eccentric muscle training would change the levels of these proteins, called cytokines, in the blood of people with MS immediately after exercise. The cytokines studied included IL-4, IL-6, IL-10, IL-17a, INF-γ, and TNF-α. These proteins are important because they help regulate inflammation and immune responses. The researchers also wanted to know if there was any connection between the levels of these proteins at rest and measures of mobility and leg strength. Twenty-seven people with MS took part in the study. Their average age was 40.1 years. In the first session, blood samples were taken to measure the baseline levels of these proteins, and various tests were conducted to assess mobility and leg strength. In the second session, participants completed an eccentric training session, and another blood sample was taken immediately after to see if there were any immediate changes in the protein levels. The results showed no significant differences in the protein levels before and after the exercise session. This suggests that a single session of eccentric muscle training does not cause an immediate inflammatory response in the blood. Therefore, this type of exercise can be safely included in rehabilitation programs for people with MS without the risk of causing harmful inflammation. Overall, the study supports the safety of eccentric muscle training for people with MS and provides valuable insights into its immediate effects on the immune system.

Correction: Application of eccentric training in various clinical populations: Protocol for a multi-centered pilot and feasibility study in people with low back pain and people with multiple sclerosis.

[This corrects the article DOI: 10.1371/journal.pone.0270875.].

Application of eccentric training in various clinical populations: Protocol for a multi-centered pilot and feasibility study in people with low back pain and people with multiple sclerosis.

Physical activity and exercise are effective approaches in prevention and therapy of multiple diseases. Although the specific characteristics of lengthening contractions have the potential to be beneficial in many clinical conditions, eccentric training is not commonly used in clinical populations with metabolic, orthopaedic, or neurologic conditions. The purpose of this pilot study is to investigate the feasibility, functional benefits, and systemic responses of an eccentric exercise program focused on the trunk and lower extremities in people with low back pain (LBP) and multiple sclerosis (MS). A six-week eccentric training program with three weekly sessions is performed by people with LBP and MS. The program consists of ten exercises addressing strength of the trunk and lower extremities. The study follows a four-group design (N = 12 per group) in two study centers (Israel and Germany): three groups perform the eccentric training program: A) control group (healthy, asymptomatic); B) people with LBP; C) people with MS; group D (people with MS) receives standard care physiotherapy. Baseline measurements are conducted before first training, post-measurement takes place after the last session both comprise blood sampling, self-reported questionnaires, mobility, balance, and strength testing. The feasibility of the eccentric training program will be evaluated using quantitative and qualitative measures related to the study process, compliance and adherence, safety, and overall program assessment. For preliminary assessment of potential intervention effects, surrogate parameters related to mobility, postural control, muscle strength and systemic effects are assessed. The presented study will add knowledge regarding safety, feasibility, and initial effects of eccentric training in people with orthopaedic and neurological conditions. The simple exercises, that are easily modifiable in complexity and intensity, are likely beneficial to other populations. Thus, multiple applications and implementation pathways for the herein presented training program are conceivable. Trial registration: DRKS00020483 (DRKS, German Clinical Trials Register; 24th January 2020 -retrospectively registered; https://www.drks.de/DRKS00020483).

Feasability of An Eccentric Isokinetic Protocol to Induce Trunk Muscle Damage: A Pilot Study.

Eccentric exercise is discussed as a treatment option for clinical populations, but specific responses in terms of muscle damage and systemic inflammation after repeated loading of large muscle groups have not been conclusively characterized. Therefore, this study tested the feasibility of an isokinetic protocol for repeated maximum eccentric loading of the trunk muscles. Nine asymptomatic participants (5 f/4 m; 34±6 yrs; 175±13 cm; 76±17 kg) performed three isokinetic 2-minute all-out trunk strength tests (1x concentric (CON), 2x eccentric (ECC1, ECC2), 2 weeks apart; flexion/extension, 60°/s, ROM 55°). Outcomes were peak torque, torque decline, total work, and indicators of muscle damage and inflammation (over 168 h). Statistics were done using the Friedman test (Dunn's post-test). For ECC1 and ECC2, peak torque and total work were increased and torque decline reduced compared to CON. Repeated ECC bouts yielded unaltered torque and work outcomes. Muscle damage markers were highest after ECC1 (soreness 48 h, creatine kinase 72 h; p<0.05). Their overall responses (area under the curve) were abolished post-ECC2 compared to post-ECC1 (p<0.05). Interleukin-6 was higher post-ECC1 than CON, and attenuated post-ECC2 (p>0.05). Interleukin-10 and tumor necrosis factor-α were not detectable. All markers showed high inter-individual variability. The protocol was feasible to induce muscle damage indicators after exercising a large muscle group, but the pilot results indicated only weak systemic inflammatory responses in asymptomatic adults.

Inter-rater and inter-session reliability of lumbar paraspinal muscle composition in a mobile MRI device.

OBJECTIVE: To assess the reliability of measurements of paraspinal muscle transverse relaxation times (T2 times) between two observers and within one observer on different time points. METHODS: 14 participants (9f/5m, 33 ± 5 years, 176 ± 10 cm, 73 ± 12 kg) underwent 2 consecutive MRI scans (M1,M2) on the same day, followed by 1 MRI scan 13-14 days later (M3) in a mobile 1.5 Tesla MRI. T2 times were calculated in T2 weighted turbo spin-echo-sequences at the spinal level of the third lumbar vertebrae (11 slices, 2 mm slice thickness, 1 mm interslice gap, echo times: 20, 40, 60, 80, 100 ms) for M. erector spinae (ES) and M. multifidius (MF). The following reliability parameter were calculated for the agreement of T2 times between two different investigators (OBS1 & OBS2) on the same MRI (inter-rater reliability, IR) and by one investigator between different MRI of the same participant (intersession variability, IS): Test-Retest Variability (TRV, Differences/Mean*100); Coefficient of Variation (CV, Standard deviation/Mean*100); Bland-Altman Analysis (systematic bias = Mean of the Differences; Upper/Lower Limits of Agreement = Bias+/-1.96*SD); Intraclass Correlation Coefficient 3.1 (ICC) with absolute agreement, as well as its 95% confidence interval. RESULTS: Mean TRV for IR was 2.6% for ES and 4.2% for MF. Mean TRV for IS was 3.5% (ES) and 5.1% (MF). Mean CV for IR was 1.9 (ES) and 3.0 (MF). Mean CV for IS was 2.5% (ES) and 3.6% (MF). A systematic bias of 1.3 ms (ES) and 2.1 ms (MF) were detected for IR and a systematic bias of 0.4 ms (ES) and 0.07 ms (MF) for IS. ICC for IR was 0.94 (ES) and 0.87 (MF). ICC for IS was 0.88 (ES) and 0.82 (MF). CONCLUSION: Reliable assessment of paraspinal muscle T2 time justifies its use for scientific purposes. The applied technique could be recommended to use for future studies that aim to assess changes of T2 times, e.g. after an intense bout of eccentric exercises.

Mobile diagnostics and consultation for the prevention of the metabolic syndrome and its secondary diseases in Brandenburg-study protocol of a regional prospective cohort study: the Mobile Brandenburg Cohort.

BACKGROUND: The metabolic syndrome (MetS) is a risk cluster for a number of secondary diseases. The implementation of prevention programs requires early detection of individuals at risk. However, access to health care providers is limited in structurally weak regions. Brandenburg, a rural federal state in Germany, has an especially high MetS prevalence and disease burden. This study aims to validate and test the feasibility of a setup for mobile diagnostics of MetS and its secondary diseases, to evaluate the MetS prevalence and its association with moderating factors in Brandenburg and to identify new ways of early prevention, while establishing a "Mobile Brandenburg Cohort" to reveal new causes and risk factors for MetS. METHODS: In a pilot study, setups for mobile diagnostics of MetS and secondary diseases will be developed and validated. A van will be equipped as an examination room using point-of-care blood analyzers and by mobilizing standard methods. In study part A, these mobile diagnostic units will be placed at different locations in Brandenburg to locally recruit 5000 participants aged 40-70 years. They will be examined for MetS and advice on nutrition and physical activity will be provided. Questionnaires will be used to evaluate sociodemographics, stress perception, and physical activity. In study part B, participants with MetS, but without known secondary diseases, will receive a detailed mobile medical examination, including MetS diagnostics, medical history, clinical examinations, and instrumental diagnostics for internal, cardiovascular, musculoskeletal, and cognitive disorders. Participants will receive advice on nutrition and an exercise program will be demonstrated on site. People unable to participate in these mobile examinations will be interviewed by telephone. If necessary, participants will be referred to general practitioners for further diagnosis. DISCUSSION: The mobile diagnostics approach enables early detection of individuals at risk, and their targeted referral to local health care providers. Evaluation of the MetS prevalence, its relation to risk-increasing factors, and the "Mobile Brandenburg Cohort" create a unique database for further longitudinal studies on the implementation of home-based prevention programs to reduce mortality, especially in rural regions. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00022764 ; registered 07 October 2020-retrospectively registered.

Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model.

In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E2 (PGE2), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE2 synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE2 concentration that was completely abrogated in mPGES-1-deficient mice. PGE2 is known to inhibit TNF-α synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-α expression. Due to the impaired PGE2 production, TNF-α expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-α resulted in an enhanced IL-1ß production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE2 production by mPGES-1 ablation enhanced the TNF-α-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.

Induction of steatohepatitis (NASH) with insulin resistance in wildtype B6 mice by a western-type diet containing soybean oil and cholesterol.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g. high-fat diets) or overweight and insulin resistance (e.g. methionine-choline-deficient diets) or they are based on monogenetic defects (e.g. ob/ob mice). In the current study, a western-type diet containing soybean oil with high n 6-PUFA and 0.75% cholesterol (SOD+Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast a soybean oil-containing western-type diet without cholesterol (SOD) induced only mild steatosis but neither hepatic inflammation nor fibrosis, weight gain or insulin resistance. Another high-fat diet mainly consisting of lard and supplemented with fructose in drinking water (LAD+Fru) resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD+Cho but livers were devoid of inflammation and fibrosis. Although both LAD+Fru- and SOD+Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD+Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. Summarizing, dietary cholesterol in SOD+Cho diet may trigger hepatic inflammation and fibrosis. SOD+Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.

Arylhydrocarbon receptor-dependent mIndy (Slc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes.

Non-alcoholic fatty liver disease is a growing problem in industrialized and developing countries. Hepatic lipid accumulation is the result of an imbalance between fatty acid uptake, fatty acid de novo synthesis, ß-oxidation and secretion of triglyceride-rich lipoproteins from the hepatocyte. A central regulator of hepatic lipid metabolism is cytosolic citrate that can either be derived from the mitochondrium or be taken up from the blood via the plasma membrane sodium citrate transporter NaCT, the product of the mammalian INDY gene (SLC13A5). mINDY ablation protects against diet-induced steatosis whereas mINDY expression is increased in patients with hepatic steatosis. Diet-induced hepatic steatosis is also enhanced by activation of the arylhyrocarbon receptor (AhR) both in humans and animal models. Therefore, the hypothesis was tested whether the mINDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the mINDY expression in primary cultures of rat hepatocytes in an AhR-dependent manner. This induction resulted in an increased citrate uptake and citrate incorporation into lipids which probably was further enhanced by the benzo[a]pyrene-dependent induction of key enzymes of fatty acid synthesis. A potential AhR binding site was identified in the mINDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the mINDY promoter by benzo[a]pyrene. This study thus identified the mINDY as an AhR target gene. AhR-dependent induction of the mINDY gene might contribute to the development of hepatic steatosis.

Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital.

Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR.