Anterior cruciate ligament: A brief narrative review of main risk factors for injury and re-injury.

Anterior cruciate ligament (ACL) injury is one of the main injuries in professional and amateur athletes of different sports. Hundreds of thousands of ACL ruptures occurs annually, and only 55% of the athletes return to competitive level, with a 15 times higher chance of suffering a second injury. 60% of these injuries occur without physical contact and since they occur in the acute process, they can cause joint effusion, muscle weakness and functional incapacity. In the long term, they can contribute to a premature process of osteoarthritis. This narrative review is of particular interest for clinicians, practitioners, coaches and athletes to understand the main factors that contribute to an injury and/or re-injury and thus, to optimize their training to reduce and/or prevent the risk of injury and/or reinjury of ACL. Therefore, we aimed reports a narrative overview of the literature surrounding communication and explore through a theoretical review, the main risk factors for an ACL injury and/or re-injury, as well as bringing practical and correct methods of training applications. The lack of theoretical/practical knowledge on the part of rehabilitation and/or training professionals may impair the treatment of an athlete and/or student. High-quality research that can testing different training methods approaches in randomized controlled trials is needed.

Aging reduces ABHD5 protein content in the adipose tissue of mice: The reversal effect of exercise.

Dysfunction of the adipose tissue metabolism is considered as a significant hallmark of aging. It has been proposed that α-ß hydrolase domain containing 5 (ABHD5) plays a critical role in the control of lipolysis. However, the role of ABHD5 in the control of lipolysis during aging or exercise is unknown. Here we combined the experimental mouse model with transcriptomic analyzes by using murine and human databases to explore the role of ABHD5 in the adipose tissue during aging and in response to exercise. Transcriptomic data revealed a downregulation of Abhd5 messenger RNA levels in the subcutaneous white adipose tissue (scWAT) over time in individuals from 20 to 69 years old. Aged mice displayed dramatic reduction of ABHD5 protein content and lipolytic-related proteins in the scWAT. Interestingly, 4 weeks of high-intensity interval training increased ABHD5 protein level and restored the lipolytic pathway in the scWAT of aged mice. Altogether, our findings demonstrated that aging affects ABHD5 content in the adipose tissue of mice and humans. Conversely, exercise increases ABHD5 activity, recovering the lipolytic activity in aged mice.

Effect of caffeine on mitochondrial biogenesis in the skeletal muscle - A narrative review.

Caffeine is one of the most widely used substances as recreational drug for performance-enhancement in sport, underpinned by a strong evidence base. Although the effects of caffeine are widely investigated within the scope of performance physiology, the molecular effects of caffeine within skeletal muscle remain unclear. Evidence from in vitro and in vivo models suggest that caffeine regulates the glucose metabolism in the skeletal muscle. Moreover, caffeine seems to stimulate CaMKII, PPARδ/ß, AMPK and PGC1α, classical markers of exercise-adaptations, including mitochondrial biogenesis and mitochondrial content. This review summarizes evidence to suggest caffeine-effects within skeletal muscle fibers, focusing on the putative role of caffeine on mitochondrial biogenesis to explore whether caffeine supplementation might be a strategy to enhance mitochondrial biogenesis.

Galectin-1 in Obesity and Type 2 Diabetes.

Galectin-1 is a carbohydrate-binding protein expressed in many tissues. In recent years, increasing evidence has emerged for the role of galectin-1 in obesity, insulin resistance and type 2 diabetes. Galectin-1 has been highly conserved through evolution and is involved in key cellular functions such as tissue maturation and homeostasis. It has been shown that galectin-1 increases in obesity, both in the circulation and in the adipose tissue of human and animal models. Several proteomic studies have independently identified an increased galectin-1 expression in the adipose tissue in obesity and in insulin resistance. Large population-based cohorts have demonstrated associations for circulating galectin-1 and markers of insulin resistance and incident type 2 diabetes. Furthermore, galectin-1 is associated with key metabolic pathways including glucose and lipid metabolism, as well as insulin signalling and inflammation. Intervention studies in animal models alter animal weight and metabolic profile. Several studies have also linked galectin-1 to the progression of complications in diabetes, including kidney disease and retinopathy. Here, we review the current knowledge on the clinical potential of galectin-1 in obesity and type 2 diabetes.

Aerobic Exercise Training Induces the Mitonuclear Imbalance and UPRmt in the Skeletal Muscle of Aged Mice.

The impairment of the mitochondrial functions is a hallmark of aging. During aging, there is a downregulation of two mechanisms strictly associated with mitochondrial integrity, including the mitonuclear imbalance (eg, imbalance in mitochondrial- versus nuclear-encoded mitochondrial proteins) and the mitochondrial unfolded protein response (UPRmt). Here, we evaluated the effects of aerobic exercise in the mitonuclear imbalance and UPRmt markers in the skeletal muscle of old mice. We combined the physiological tests, molecular and bioinformatic analyzes to evaluate the effects of 4 weeks of aerobic exercise training on mitonuclear imbalance and UPRmt markers in the skeletal muscle of young (2 months) and aged (24 months) C57BL/6J mice. Initially, we found that aging reduced several mitochondrial genes in the gastrocnemius muscle, and it was accompanied by the low levels of UPRmt markers, including Yme1l1 and Clpp mRNA. As expected, physical training improved the whole-body metabolism and physical performance of aged mice. The aerobic exercise increased key proteins involved in the mitochondrial biogenesis/functions (VDAC and SIRT1) along with mitochondrial-encoded genes (mtNd1, mtCytB, and mtD-Loop) in the skeletal muscle of old mice. Interestingly, aerobic exercise induced the mitonuclear imbalance, increasing MTCO1/ATP5a ratio and UPRmt markers in the skeletal muscle, including HSP60, Lonp1, and Yme1L1 protein levels in the gastrocnemius muscle of aged mice. These data demonstrate that aerobic exercise training induced mitonuclear imbalance and UPRmt in the skeletal muscle during aging. These phenomena could be involved in the improvement of the mitochondrial metabolism and oxidative capacity in aged individuals.

TGF-ß1 downregulation in the hypothalamus of obese mice through acute exercise.

Obesity and aging lead to abnormal transforming growth factor-ß1 (TGF-ß1) signaling in the hypothalamus, triggering the imbalance on glucose metabolism and energy homeostasis. Here, we determine the effect of acute exercise on TGF-ß1 expression in the hypothalamus of two models of obesity in mice. The bioinformatics analysis was performed to evaluate the correlation between hypothalamic Tgf-ß1 messenger RNA (mRNA) and genes related to thermogenesis in the brown adipose tissue (BAT) by using a large panel of isogenic BXD mice. Thereafter, leptin-deficient (ob/ob) mice and obese C57BL/6 mice fed on a high-fat diet (HFD) were submitted to the acute exercise protocol. Transcriptomic analysis by using BXD mouse reference population database revealed that hypothalamic Tgf-ß1 mRNA is negatively correlated with genes related to thermogenesis in brown adipose tissue of BXD mice, such as peroxisome proliferator-activated receptor gamma coactivator and is positively correlated with respiratory exchange ratio. In agreement with these results, leptin-deficient (ob/ob) and HFD-fed mice displayed high levels of Tgf-ß1 mRNA in the hypothalamus and reduction of Pgc1α mRNA in BAT. Interestingly, an acute exercise session reduced TGF-ß1 expression in the hypothalamus, increased Pgc1α mRNA in the BAT and reduced food consumption in obese mice. Our results demonstrated that acute physical exercise suppressed hypothalamic TGF-ß1 expression, increasing Pgc1α mRNA in BAT in obese mice.

The role of sphingosine-1-phosphate in skeletal muscle: Physiology, mechanisms, and clinical perspectives.

Sphingolipids were discovered more than a century ago and were simply considered as a class of cell membrane lipids for a long time. However, after the discovery of several intracellular functions and their role in the control of many physiological and pathophysiological conditions, these molecules have gained much attention. For instance, the sphingosine-1-phosphate (S1P) is a circulating bioactive sphingolipid capable of triggering strong intracellular reactions through the family of S1P receptors (S1PRs) spread in several cell types and tissues. Recently, the role of S1P in the control of skeletal muscle metabolism, atrophy, regeneration, and metabolic disorders has been widely investigated. In this review, we summarized the knowledge of S1P and its effects in skeletal muscle metabolism, highlighting the role of S1P/S1PRs axis in skeletal muscle regeneration, fatigue, ceramide accumulation, and insulin resistance. Finally, we discussed the physical exercise role in S1P/S1PRs signaling in skeletal muscle cells, and how this nonpharmacological strategy may be prospective for future investigations due to its ability to increase S1P levels.

Nicotinamide riboside induces a thermogenic response in lean mice.

AIMS: Nicotinamide Riboside (NR) is a NAD+ booster with wide physiological repercussion including the improvement on glucose and lipid homeostasis, increasing the life expectancy in mammals. However, the effects of NR on metabolism are only partially known. Here, we evaluated the effects of NR on the thermogenic response, highlighting the brown adipose tissue (BAT) in lean mice. MAIN METHODS: Male C57BL/67 mice were supplement with NR (400 mg/Kg/day) during 5 weeks. The Comprehensive Lab Animal Monitoring System (CLAMS) and thermographic images were used to evaluated the physiological effects of NR treatment. The BAT were extracted and analyzed by Western Blotting and qPCR. Also, bioinformatics analyses were performed to establish the connection between the NAD+ synthesis pathway in BAT and thermogenic response in several isogenic strains of BXD mice. KEY FINDINGS: Transcriptomic analysis revealed that genes involved in NAD+ synthesis (Nampt and Nmnat1) in the BAT were negatively correlated with body weight and fat mass. The heat map showed a strong positive correlation between Nampt and Ucp1 mRNA in BAT and body temperature in several strains of BXD lean mice. The experimental approaches demonstrated that oral NR supplementation reduced the abdominal visceral fat depots, with discrete impact on oxygen consumption in C57BL/6J mice. Interestingly, NR significantly increased the body temperature, and this phenomenon was accompanied by high levels of UCP1 protein content and Pgc1α mRNA in BAT. SIGNIFICANCE: This study demonstrated the oral NR supplementation was sufficient to induce the thermogenic response in lean mice changing the BAT metabolism.

Exercise activates the hypothalamic S1PR1-STAT3 axis through the central action of interleukin 6 in mice.

Hypothalamic sphingosine-1-phosphate receptor 1 (S1PR1), the G protein-coupled receptor 1 of sphingosine-1-phosphate, has been described as a modulator in the control of energy homeostasis in rodents. However, this mechanism is still unclear. Here, we evaluate the role of interleukin 6 (IL-6) associated with acute physical exercise in the control of the hypothalamic S1PR1-signal transducer and activator of transcription 3 (STAT3) axis. Acute exercise session and an intracerebroventricular IL-6 injection increased S1PR1 protein content and STAT3 phosphorylation in the hypothalamus of lean and obese mice accompanied by a reduction in food consumption. Transcriptome analysis indicated a strong positive correlation between Il-6 and S1pr1 messenger RNA in several tissues of genetically diverse BXD mice strains and humans, including in the hypothalamus. Interestingly, exercise failed to stimulate the S1PR1-STAT3 axis in IL-6 knockout mice and the disruption of hypothalamic-specific IL-6 action blocked the anorexigenic effects of exercise. Taken together, our results indicate that physical exercise modulates the S1PR1 protein content in the hypothalamus, through the central action of IL-6.

The role of cathepsin B in autophagy during obesity: A systematic review.

White adipose tissue (WAT) regulates energy homeostasis by releasing adipokines and modulating cell maintenance. Nutrient excess affects adipocyte hypertrophy directly in WAT by increasing excessively the activity of autophagy systems, generating proinflammatory markers and increasing infiltration of macrophages, causing metabolic diseases such as obesity and diabetes. Evidences suggest that cathepsin B (CTSB), a papain-like cysteine peptidase protein, can modulate autophagy processes in adipocytes. This review will focus on the role of CTSB in autophagy under conditions of obesity.

ß-hydroxy-ß-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review.

ß-Hydroxy-ß-methylbutyrate free acid (HMB-FA) has been suggested to accelerate the regenerative capacity of skeletal muscle after high-intensity exercise and attenuate markers of skeletal muscle damage. Herein a systematic review on the use of HMB-FA supplementation as an ergogenic aid to improve measures of muscle recovery, performance, and hypertrophy after resistance training was conducted. This review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We included randomized, double-blinded, placebo-controlled trials investigating the effects of HMB-FA supplementation in conjunction with resistance exercise in humans. The search was conducted using Medline and Google Scholar databases for the terms beta-hydroxy-beta-methylbutyrate, HMB free acid, exercise, resistance exercise, strength training, and HMB supplementation. Only research articles published from 1996 to 2016 in English language were considered for the analysis. Nine studies met the criteria for inclusion in the analyses. Most studies included resistance-trained men, and the primary intervention strategy involved administration of 3g of HMB-FA per day. In conjunction with resistance training, HMB-FA supplementation may attenuate markers of muscle damage, augment acute immune and endocrine responses, and enhance training-induced muscle mass and strength. HMB-FA supplementation may also improve markers of aerobic fitness when combined with high-intensity interval training. Nevertheless, more studies are needed to determine the overall efficacy of HMB-FA supplementation as an ergogenic aid.

Chronic exercise reduces hypothalamic transforming growth factor-ß1 in middle-aged obese mice.

Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-ß (TGF-ß1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-ß1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-ß1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-ß1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-ß1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.

Physical exercise increases Sestrin 2 protein levels and induces autophagy in the skeletal muscle of old mice.

Sestrins and autophagy deficiencies are associated with several aging-related organic dysfunctions and metabolic disorders. Here we evaluate the effects of acute exercise on Sestrin 2 (Sesn2) protein content and autophagy markers in the skeletal muscle of experimental models of aging. Twenty-four months-old C57BL/6J male mice were submitted to a single bout of swimming exercise and the gastrocnemius muscle was evaluated by Western blot. Transcriptomic and phenotypic analysis were also performed by using strains of genetically-diverse BXD mice. The bioinformatics analysis showed a negative correlation between Sesn2 mRNA levels in the skeletal muscle and body weight gain, plasma triglycerides and fasting glucose and positive correlation with several autophagic markers in the muscle of BXD mice. Consistent with these findings, low levels of Sesn2 protein content were observed in the gastrocnemius muscle of C57BL/6J old mice when compared to young group. Interestingly, the acute aerobic exercise induced Sesn2 accumulation and modulated several markers of autophagy in the gastrocnemius muscle old mice, including unc-51-like kinase-1 (Ulk1) phosphorylation and the protein levels of Atg5, Atg7, p62 and LC3-II. Finally, exercise increased insulin sensitivity in old animals, as demonstrated by kITT. Taken together, these findings demonstrated the acutely, aerobic physical exercise recovers Sestrin 2 protein content and induces autophagy in the skeletal muscle of old mice, contributing with the improvement of insulin sensitivity an aging animal model.

Ursolic acid and mechanisms of actions on adipose and muscle tissue: a systematic review.

This systematic review aimed at addressing the ursolic acid actions as an adjunctive treatment of the obesity-mediated metabolic abnormalities. To explore our aims, we used the literature search including clinical and animal studies using the Medline and Google Scholar (up to December 2015). Out of 63 screened studies, 17 presented eligibility criteria, such as the use of ursolic acid on adiposity, energy expenditure and skeletal muscle mass in mice and humans. In the literature, we found that several physiological and molecular mechanisms are implicated in the effects of ursolic acid on obesity, energy expenditure, hepatic steatosis, skeletal muscle mass loss and physical fitness, such as (1) increase of thermogenesis by modulation adipocyte transcription factors, activation of 5' adenosine monophosphate-activated protein kinase and overexpression of the uncoupling protein 1 thermogenic marker; (2) enhancement of skeletal muscle mass by activation in bloodstream growth hormone and insulin-like growth factor-1 concentrations secretion, as well as in the activation of mammalian target of rapamycin and inhibition of ring-finger protein-1; and (3) improvement of physical fitness by skeletal muscle proliferator-activated receptor gamma co-activator alpha and sirtuin 1 expression. Therefore, supplementation with ursolic acid may be an adjunctive therapy for prevention and treatment of obesity-mediated and muscle mass-mediated metabolic consequences.

Hypothalamic S1P/S1PR1 axis controls energy homeostasis.

Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.

Acute exercise suppresses hypothalamic PTP1B protein level and improves insulin and leptin signaling in obese rats.

Hypothalamic inflammation is associated with insulin and leptin resistance, hyperphagia, and obesity. In this scenario, hypothalamic protein tyrosine phosphatase 1B (PTP1B) has emerged as the key phosphatase induced by inflammation that is responsible for the central insulin and leptin resistance. Here, we demonstrated that acute exercise reduced inflammation and PTP1B protein level/activity in the hypothalamus of obese rodents. Exercise disrupted the interaction between PTP1B with proteins involved in the early steps of insulin (IRß and IRS-1) and leptin (JAK2) signaling, increased the tyrosine phosphorylation of these molecules, and restored the anorexigenic effects of insulin and leptin in obese rats. Interestingly, the anti-inflammatory action and the reduction of PTP1B activity mediated by exercise occurred in an interleukin-6 (IL-6)-dependent manner because exercise failed to reduce inflammation and PTP1B protein level after the disruption of hypothalamic-specific IL-6 action in obese rats. Conversely, intracerebroventricular administration of recombinant IL-6 reproduced the effects of exercise, improving hypothalamic insulin and leptin action by reducing the inflammatory signaling and PTP1B activity in obese rats at rest. Taken together, our study reports that physical exercise restores insulin and leptin signaling, at least in part, by reducing hypothalamic PTP1B protein level through the central anti-inflammatory response.