Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes. (AU)

Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning.

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.

Futile cycle of ß-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy.

Total absence of adipose tissue (lipoatrophy) is associated with the development of severe metabolic disorders including hepatomegaly and fatty liver. Here, we sought to investigate the impact of severe lipoatrophy induced by deletion of peroxisome proliferator-activated receptor gamma (PPARγ) exclusively in adipocytes on lipid metabolism in mice. Untargeted lipidomics of plasma, gastrocnemius and liver uncovered a systemic depletion of the essential linoleic (LA) and α-linolenic (ALA) fatty acids from several lipid classes (storage lipids, glycerophospholipids, free fatty acids) in lipoatrophic mice. Our data revealed that such essential fatty acid depletion was linked to increased: 1) capacity for liver mitochondrial fatty acid ß-oxidation (FAO), 2) citrate synthase activity and coenzyme Q content in the liver, 3) whole-body oxygen consumption and reduced respiratory exchange rate in the dark period, and 4) de novo lipogenesis and carbon flux in the TCA cycle. The key role of de novo lipogenesis in hepatic steatosis was evidenced by an accumulation of stearic, oleic, sapienic and mead acids in liver. Our results thus indicate that the simultaneous activation of the antagonic processes FAO and de novo lipogenesis in liver may create a futile metabolic cycle leading to a preferential depletion of LA and ALA. Noteworthy, this previously unrecognized cycle may also explain the increased energy expenditure displayed by lipoatrophic mice, adding a new piece to the metabolic regulation puzzle in lipoatrophies.

Adipocyte-specific mTORC2 deficiency impairs BAT and iWAT thermogenic capacity without affecting glucose uptake and energy expenditure in cold-acclimated mice.

Deletion of mechanistic target of rapamycin complex 2 (mTORC2) essential component rapamycin insensitive companion of mTOR (Rictor) by a Cre recombinase under control of the broad, nonadipocyte-specific aP2/FABP4 promoter impairs thermoregulation and brown adipose tissue (BAT) glucose uptake on acute cold exposure. We investigated herein whether adipocyte-specific mTORC2 deficiency affects BAT and inguinal white adipose tissue (iWAT) signaling, metabolism, and thermogenesis in cold-acclimated mice. For this, 8-wk-old male mice bearing Rictor deletion and therefore mTORC2 deficiency in adipocytes (adiponectin-Cre) and littermates controls were either kept at thermoneutrality (30 ± 1°C) or cold-acclimated (10 ± 1°C) for 14 days and evaluated for BAT and iWAT signaling, metabolism, and thermogenesis. Cold acclimation inhibited mTORC2 in BAT and iWAT, but its residual activity is still required for the cold-induced increases in BAT adipocyte number, total UCP-1 content and mRNA levels of proliferation markers Ki67 and cyclin 1 D, and de novo lipogenesis enzymes ATP-citrate lyase and acetyl-CoA carboxylase. In iWAT, mTORC2 residual activity is partially required for the cold-induced increases in multilocular adipocytes, mitochondrial mass, and uncoupling protein 1 (UCP-1) content. Conversely, BAT mTORC1 activity and BAT and iWAT glucose uptake were upregulated by cold independently of mTORC2. Noteworthy, the impairment in BAT and iWAT total UCP-1 content and thermogenic capacity induced by adipocyte mTORC2 deficiency had no major impact on whole body energy expenditure in cold-acclimated mice due to a compensatory activation of muscle shivering. In conclusion, adipocyte mTORC2 deficiency impairs, through different mechanisms, BAT and iWAT total UCP-1 content and thermogenic capacity in cold-acclimated mice, without affecting glucose uptake and whole body energy expenditure.NEW & NOTEWORTHY BAT and iWAT mTORC2 is inhibited by cold acclimation, but its residual activity is required for cold-induced increases in total UCP-1 content and thermogenic capacity, but not glucose uptake and mTORC1 activity. The impaired BAT and iWAT total UCP-1 content and thermogenic capacity induced by adipocyte mTORC2 deficiency are compensated by activation of muscle shivering in cold-acclimated mice.

Physical exercise for the management of systemic autoimmune myopathies: recent findings, and future perspectives.

PURPOSE OF REVIEW: The aim of this review is to present the main pieces of evidence, recent literature and to present future perspectives on the use of exercise/physical training in the treatment and improvement of the quality of life of patients with systemic autoimmune myopathies. RECENT FINDINGS: In the last decades, knowledge about the relevance of physical exercise training in preventing and treating chronic diseases and improving quality of life has grown. Following the global trend exemplified by the expression 'exercise is medicine', the importance of exercise/physical training has also grown in myopathies. However, the science of exercise has a lot to collaborate on and improve patients' quality of life with myopathies by appropriating new technological tools, including accessible and low-cost devices and smartphone apps. SUMMARY: Physical exercise, as already consolidated in the literature, is an effective, well tolerated, and low-cost strategy for patients with myopathies. The use of wearable devices, smartphone apps, and online training prescriptions must accompany the global scenario, bringing new research fields and expanding the options for access to training for the individualized basis, and prescribed by qualified professionals.

PPARγ-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activity.

The nutrient sensors peroxisome proliferator-activated receptor γ (PPARγ) and mechanistic target of rapamycin complex 1 (mTORC1) closely interact in the regulation of adipocyte lipid storage. The precise mechanisms underlying this interaction and whether this extends to other metabolic processes and the endocrine function of adipocytes are still unknown. We investigated herein the involvement of mTORC1 as a mediator of the actions of the PPARγ ligand rosiglitazone in subcutaneous inguinal white adipose tissue (iWAT) mass, endocrine function, lipidome, transcriptome and branched-chain amino acid (BCAA) metabolism. Mice bearing regulatory associated protein of mTOR (Raptor) deletion and therefore mTORC1 deficiency exclusively in adipocytes and littermate controls were fed a high-fat diet supplemented or not with the PPARγ agonist rosiglitazone (30 mg/kg/day) for 8 weeks and evaluated for iWAT mass, lipidome, transcriptome (Rnaseq), respiration and BCAA metabolism. Adipocyte mTORC1 deficiency not only impaired iWAT adiponectin transcription, synthesis and secretion, PEPCK mRNA levels, triacylglycerol synthesis and BCAA oxidation and mRNA levels of related proteins but also completely blocked the upregulation in these processes induced by pharmacological PPARγ activation with rosiglitazone. Mechanistically, adipocyte mTORC1 deficiency impairs PPARγ transcriptional activity by reducing PPARγ protein content, as well as by downregulating C/EBPα, a co-partner and facilitator of PPARγ. In conclusion, mTORC1 and PPARγ are essential partners involved in the regulation of subcutaneous adipose tissue adiponectin production and secretion and BCAA oxidative metabolism.

Interleukin-6 and the Gut Microbiota Influence Melanoma Progression in Obese Mice.

There is a strong correlation between obesity and cancer. Here, we investigated the influence of IL-6 and gut microbiota of obese mice in melanoma development. We first evaluated B16F10 melanoma growth in preclinical models for obesity: mice deficient for leptin (ob/ob) or adiponectin (AdpKO) and in wild-type mice (WT, C57BL/6J) fed a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. The survival rates of ob/ob and HFD-fed mice were lower than those of their respective controls. AdpKO mice also died earlier than WT control mice. We then verified the involvement of IL-6 signaling in obese mice that were inoculated with melanoma cells. Both ob/ob and AdpKO mice had higher circulating IL-6 levels than wild-type mice. Melanoma tumor volumes in IL-6 KO mice fed an HFD were reduced compared to those of WT mice subjected to the same diet. Also evaluated the effect of microbiota in tumor development. Cohousing and fecal matter transfer experiments revealed that microbiota from ob/ob mice can stimulate tumor development in lean WT mice. Taken together, our data show that in some conditions IL-6 and the gut microbiota are key mediators that link obesity and melanoma.

Mild-cold water swimming does not exacerbate white adipose tissue browning and brown adipose tissue activation in mice.

The present study investigated the effects of swimming physical training either thermoneutral or below thermoneutral water temperature on white (WAT) and brown (BAT) adipose tissue metabolism, morphology, and function. C57BL/6J male mice (n = 40; weight 25.3 ± 0.1 g) were divided into control (CT30), cold control (CT20), trained (TR30), and cold trained (TR20) groups. Swimming training consisted of 30-min exercise at 30°C (control) or 20°C (cold) water temperature. After 8-week training, adipose tissues were excised and inguinal (ingWAT) and BAT were processed for histology, lipolysis, and protein contents of total OXPHOS, PGC1α, and UCP1 by western blotting analysis. Swimming training reduced body weight gain independently of water temperature (P < 0.05). ingWAT mass was decreased for TR30 in comparison to other groups (P < 0.05), while for BAT, there was a significant increase in CT20 in relation to CT30, and both trained groups were significantly increased in relation to control groups (P < 0.05). ingWAT mean adipocyte area was smaller for trained groups, and seemed to present multilocular adipocytes. Lipolytic activity and protein content of UCP1, PGC1α, and mitochondrial markers were increased in trained groups for ingWAT (P < 0.05), independent of water temperature (P > 0.05), and these patterns were not observed for BAT (P > 0.05). Our findings suggest that mild-cold water exposure and swimming physical exercise seem to, independently, promote browning in ingWAT with no effects on BAT; however, the association of exercise and mild-cold water did not exacerbate these effects.

Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1.

Aging impairs tissue repair. This is pronounced in skeletal muscle, whose regeneration by muscle stem cells (MuSCs) is robust in young adult animals but inefficient in older organisms. Despite this functional decline, old MuSCs are amenable to rejuvenation through strategies that improve the systemic milieu, such as heterochronic parabiosis. One such strategy, exercise, has long been appreciated for its benefits on healthspan, but its effects on aged stem cell function in the context of tissue regeneration are incompletely understood. Here we show that exercise in the form of voluntary wheel running accelerates muscle repair in old animals and improves old MuSC function. Through transcriptional profiling and genetic studies, we discovered that the restoration of old MuSC activation ability hinges on restoration of Cyclin D1, whose expression declines with age in MuSCs. Pharmacologic studies revealed that Cyclin D1 maintains MuSC activation capacity by repressing TGFß signaling. Taken together, these studies demonstrate that voluntary exercise is a practicable intervention for old MuSC rejuvenation. Furthermore, this work highlights the distinct role of Cyclin D1 in stem cell quiescence.

Gut Microbiota and Intestinal Epithelial Myd88 Signaling Are Crucial for Renal Injury in UUO Mice.

Increasing evidence shows the essential participation of gut microbiota in human health and diseases by shaping local and systemic immunity. Despite an accumulating body of studies showing that chronic kidney disease (CKD) is closely associated with disturbances in the composition of gut microbiota, it remains unclear the importance of gut microbiota in the onset and development of CKD. For the purpose of untangling the role of gut microbiota in CKD, gut microbiota was depleted with a pool of broad-spectrum antibiotics in mice submitted to unilateral ureteral obstruction (UUO). Depletion of gut microbiota significantly decreased levels of proinflammatory cytokines and fibrosis markers, attenuating renal injury. Additionally, to study whether the pathogenic role of gut microbiota is dependent of microbial-host crosstalk, we generated mice lacking Myd88 (myeloid differentiation primary response gene 8) expression in intestinal epithelial cells (IECs) and performed UUO. The absence of Myd88 in IECs prevented a bacterial burden in mesenteric lymph nodes as observed in WT mice after UUO and led to lower expression of proinflammatory cytokines and chemokines, reducing deposition of type I collagen and, ultimately, attenuating renal damage. Therefore, our results suggest that the presence of gut microbiota is crucial for the development of CKD and may be dependent of Myd88 signaling in IECs, which appears to be essential to maturation of immune cells intimately involved in aggravation of inflammatory scenarios.

Effects of Walking Training with Restricted Blood Flow on HR and HRV Kinetics and HRV Recovery.

The aim of this study was to investigate the effects of walking training with and without blood flow restriction (BFR) on heart rate (HR) and heart rate variability (HRV) kinetics and HRV recovery. Twenty-one men (53.5±3.2 years; 82.4±13.5 kg; 168.5±7.2 cm) were randomly assigned to two training groups: walk training group with (BFR-W; n=11) and without (NOR-W; n=10) BFR. Before and after training, all subjects underwent body composition evaluation, incremental test, and one constant load test. Walking training was performed 3 times/week, during 6 weeks. Each session was composed by 5 sets of 3-min walking and 1-min rest between the sets. All parameters of HR on- and off-kinetics and RMSSD15 0 parameter of HRV on-kinetics were improved for BFR-W group after training (p<0.05), with an interaction effect for HR on-kinetics parameters and RMSSD15 0 parameter (p<0.05). Also, parameters of time and frequency domain of HRV recovery were also improved in BFR-W after training (p<0.05), with no interaction effect (p>0.05). Additionally, in BFR-W group, RMSSD60s values were improved in some moments after training (p<0.05). Therefore, this study demonstrates that a 6-week walking training with BFR improved cardiac autonomic responses on the onset and recovery of exercise.

TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is considered an inflammatory disease in which toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy-associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover.

Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche?

Chronic inflammation impairs skeletal muscle regeneration. Although many cells are involved in chronic inflammation, macrophages seem to play an important role in impaired muscle regeneration since these cells are associated with skeletal muscle stem cell (namely, satellite cells) activation and fibro-adipogenic progenitor cell (FAP) survival. Specifically, an imbalance of M1 and M2 macrophages seems to lead to impaired satellite cell activation, and these are the main cells that function during skeletal muscle regeneration, after muscle damage. Additionally, this imbalance leads to the accumulation of FAPs in skeletal muscle, with aberrant production of pro-fibrotic factors (e.g., extracellular matrix components), impairing the niche for proper satellite cell activation and differentiation. Treatments aiming to block the inflammatory pro-fibrotic response are partially effective due to their side effects. Therefore, strategies reverting chronic inflammation into a pro-regenerative pattern are required. In this review, we first describe skeletal muscle resident macrophage ontogeny and homeostasis, and explain how macrophages are replenished after muscle injury. We next discuss the potential role of chronic physical activity and exercise in restoring the M1 and M2 macrophage balance and consequently, the satellite cell niche to improve skeletal muscle regeneration after injury.

Acute exercise elicits differential expression of insulin resistance genes in the skeletal muscle of patients with polycystic ovary syndrome.

OBJECTIVE: This study aimed to explore the role of acute exercise on skeletal muscle gene expression related to insulin resistance in patients with polycystic ovary syndrome (PCOS) and controls. METHODS: Four obese women with PCOS and four body mass index (BMI)-matched controls (CTRL) participated in this study. After an overnight fast, the subjects underwent a single 40-min bout of aerobic exercise. Muscle samples were obtained from vastus lateralis at baseline and 60 min after exercise. The expression of a panel of insulin resistance genes was evaluated by a quantitative PCR array system. Network-based analyses were performed to interpret transcriptional changes occurring before and after the exercise challenge. RESULTS: Overall, differentially expressed genes associated with mitochondria function and peroxisome proliferator-activated receptor signalling were identified. At baseline, there was a significant upregulation of six genes exclusively in PCOS (i.e. NFKBIA, MAPK3, PPARGC1A, GAPDH, ACTB and PPARA). Twelve genes were upregulated in CTRL after a single bout of aerobic exercise (i.e. LEPR, CXCR4, CCR5, IL-18R1, CRLF2, ACACA, CEBPA, PPARGC1A, UCP1, TNFRSF1B, TLR4 and IKBKB). After the exercise session, three genes were upregulated in PCOS (i.e. SOCS3, NAMPT and IL-8), whilst IL-6 was upregulated in both groups after exercise. CONCLUSIONS: This study provides novel evidence on the effects of acute exercise on insulin resistance genes in skeletal muscle of PCOS. The differentially expressed genes reported herein could be further investigated as targets for therapeutic interventions aimed at improving insulin resistance in this syndrome.

GLUT4 translocation is not impaired after acute exercise in skeletal muscle of women with obesity and polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to examine the effects of acute exercise on insulin signaling in skeletal muscle of women with polycystic ovary syndrome (PCOS) and controls (CTRL). METHODS: Fifteen women with obesity and PCOS and 12 body mass index-matched CTRL participated in this study. Subjects performed a 40-min single bout of exercise. Muscle biopsies were performed before and 60 min after exercise. Selected proteins were assessed by Western blotting. RESULTS: CTRL, but not PCOS, showed a significant increase in PI3-k p85 and AS160 Thr 642 after a single bout of exercise (P = 0.018 and P = 0.018, respectively). Only PCOS showed an increase in Akt Thr 308 and AMPK phosphorylation after exercise (P = 0.018 and P = 0.018, respectively). Total GLUT4 expression was comparable between groups (P > 0.05). GLUT4 translocation tended to be significantly higher in both groups after exercise (PCOS: P = 0.093; CTRL: P = 0.091), with no significant difference between them (P > 0.05). CONCLUSIONS: A single bout of exercise elicited similar GLUT4 translocation in skeletal muscle of PCOS and CTRL, despite a slightly differential pattern of protein phosphorylation. The absence of impairment in GLUT4 translocation suggests that PCOS patients with obesity and insulin resistance may benefit from exercise training.

Safety and feasibility of maximal physical testing in rheumatic diseases: a cross-sectional study with 5,910 assessments.

The purpose of the study was to report on the safety and feasibility of the application of maximal physical tests in a heterogeneous cohort of rheumatic patients. This is a 5-year retrospective descriptive report on the incidence of events associated with maximal physical testing from 536 patients, totalizing 5,910 tests. Tests were classified as cardiopulmonary, muscle strength, and physical functioning tests. Any adverse events during the tests and limiting factors incurring in tests cancellation were reported. Eighteen out of 641 cardiopulmonary exercise tests had an adverse occurrence, with cardiac disturbance (1.4% of total tests) being the most prevalent. Moreover, 14 out of 641 tests were not feasible. Out of 3,478 tests comprising leg press, bench press, knee extension, and handgrip tests, 15 tests had an adverse event. The most common occurrence was joint pain (0.4% of total tests), which was also the most frequent factor precluding testing (0.5% of total tests). Forty-five out of 3,478 (1.3%) of the tests were not feasible. There was a very low incidence of events (0.2%) during the physical functioning tests. Joint pain was the only adverse event during the tests, whereas physical limitations were the most important barriers for the execution of the tests (1.1% of total tests). The incidence of limiting events in this test was 1.6% (n = 29). This report brings new data on the safety and feasibility of maximal physical testing in rheumatic patients. The physical tests described in this study may be applied for testing rheumatic patients both in research and clinical setting.

The effects of exercise on lipid profile in systemic lupus erythematosus and healthy individuals: a randomized trial.

The aim of the present study was to evaluate the effects of an exercise training program on lipid profile and composition of high-density lipoprotein (HDL) subfractions in systemic lupus erythematosus (SLE) patients and healthy controls. A 12-week, randomized trial was conducted. Thirty-three physically inactive SLE patients were randomly assigned into two groups: trained (SLE-TR, n = 17) and non-trained (SLE-NT, n = 16). A gender-, BMI-, and age-matched healthy control groups (C-TR, n = 11) also underwent the exercise program. Subjects were assessed at baseline (Pre) and 12 weeks after the 3-month exercise training program (Post) for lipid profile (HDL, low-density lipoprotein, very low-density lipoprotein, and total cholesterol and triglycerides levels) and composition of the HDL subfractions HDL2 and HDL3. SLE patients showed significantly lower contents of Apo A-I, phospholipid, and triglyceride in the HDL3 subfraction (p < 0.05, between-group comparisons) than healthy controls at baseline. The exercise training program did not affect any of the parameters in the SLE-TR group (p > 0.05, within-group comparisons), although there was a trend toward decreased circulating Apo B levels (p = 0.06, ES = -0.3, within-group comparison). In contrast, the same exercise training program was effective in increasing contents of cholesterol, triglyceride, and phospholipid in the HDL2 subfraction in the C-TR group (p = 0.036, ES = 2.06; p = 0.038, ES = 1.77; and p = 0.0021, ES = 2.37, respectively, within-group comparisons), whereas no changes were observed in the composition of the HDL3 subfraction. This study showed that SLE patients have a less effective response to a 12-week exercise training program than healthy individuals, with regard to lipid profile and chemical composition of HDL subfractions. These results reinforce the need for further studies to define the optimal training protocol to improve lipid profile and particularly the HDL composition in these patients (registered at clinicaltrials.gov as NCT01515163).

Safety and possible effects of low-intensity resistance training associated with partial blood flow restriction in polymyositis and dermatomyositis.

INTRODUCTION: Our aim was to evaluate the safety and efficacy of a low-intensity resistance training program combined with partial blow flow restriction (BFR training) in a cohort of patients with polymyositis (PM) and dermatomyositis (DM). METHODS: In total, 13 patients with PM and DM completed a 12-week twice a week low-intensity (that is, 30% one-repetition-maximum (1RM)) resistance exercise training program combined with partial blood flow restriction (BFR). Assessments of muscle strength, physical function, quadriceps cross sectional (CSA) area, health-related quality of life, and clinical and laboratory parameters were assessed at baseline and after the intervention. RESULTS: The BFR training program was effective in increasing the maximal dynamic strength in both the leg-press (19.6%, P <0.001) and knee-extension exercises (25.2% P <0.001), as well as in the timed-stands (15.1%, P <0.001) and timed-up-and-go test (-4.5%, P =0.002). Quadriceps CSA was also significantly increased after the intervention (4.57%, P =0.01). Similarly, all of the components of the Short Form-36 Health Survey, the Health Assessment Questionnaire scores, and the patient- and physician reported Visual Analogue Scale were significantly improved after training (P <0.05). Importantly, no clinical evidence or any other self-reported adverse event were found. Laboratory parameters (creatine kinase and aldolase) were also unchanged (P >0.05) after the intervention. CONCLUSIONS: We demonstrated that a 12-week supervised low-intensity resistance training program associated with partial blood flow restriction may be safe and effective in improving muscle strength and function as well as muscle mass and health-related quality of life in patients with PM and DM. TRIAL REGISTRATION: Clinicaltrials.gov NCT01501019. Registered November 29, 2011.

Exercise training can attenuate the inflammatory milieu in women with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation. This study sought to assess the effects of an exercise training program on cytokines and soluble TNF receptors (sTNFRs) in response to acute exercise in SLE women. Eight SLE women and 10 sex-, age-, and body mass index-comparable healthy controls (HC) participated in this study. Before and after a 12-wk aerobic exercise training program, cytokines and sTNFRs were assessed at rest and in response to single bouts of acute moderate/intense exercise. HC performed the acute exercise bouts only at baseline. After the exercise training program, there was a decrease in resting TNFR2 levels (P = 0.025) and a tend to reduction interleukin (IL)-10 levels (P = 0.093) in SLE. The resting levels of IL-6, IL-10, and TNF-α after the exercise training in SLE reached HC levels (P > 0.05). In response to a single bout of acute moderate exercise, the area under the curve (AUC) of IL-10 was significantly reduced after the exercise training program in SLE (P = 0.043), and the AUC of IL-10, IL-6, TNF-α, and sTNFR1 of SLE approached control values (P > 0.05). In response to a single bout of acute intense exercise, the AUC of IL-10 was significantly reduced in SLE (P = 0.015). Furthermore, the AUC of sTNFR2 tended to decrease after exercise training program in SLE (P = 0.084), but it did not reach control values (P = 0.001). An aerobic exercise training program attenuated the inflammatory milieu in SLE women, revealing a novel homeostatic immunomodulatory role of exercise in an autoimmunity condition.