Catabolic Conditions Research Articles

Parathyroid hormone stimulates adipose tissue browning: a pathway to muscle wasting.

Studying organ-to-organ communications (i.e. crosstalk) uncovers mechanisms regulating metabolism in several tissues. What is missing is identification of mediators of different catabolic conditions contributing to losses of adipose and muscle tissues. Identifying mediators involved in organ-to-organ crosstalk could lead to innovative therapeutic strategies because several disorders such as chronic kidney disease (CKD), cancer cachexia, and other catabolic conditions share signals of worsening metabolism and increased risk of mortality. A recent breakthrough published in Cell Metabolism leads to the conclusion that parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) cause 'browning' of white adipose tissue plus energy production via activation of uncoupling protein-1. Browning was associated with muscle wasting in mouse models of cancer and CKD. The pathway to browning includes PTH/PTHrP activation of protein kinase A (PKA) and lost muscle mass via the ubiquitin proteasome proteolytic system (UPS). The results suggest that crosstalk between muscle and fat contributes in a major way to tissue catabolism. The pathway initiated by PTH or PTHrP is novel and it suggests potential interrelationships that control metabolism in other catabolic conditions. Identifying how the parathyroid hormone-PKA-UPS axis relates to obesity, type 2 diabetes, and other insulin-resistant conditions remains unclear.

Impact of Downhill Running on Proteasome Content in Mouse Skeletal Muscle

PURPOSE: The proteasome consists of two main forms, the standard proteasome and its inducible counterpart, the immunoproteasome. In skeletal muscle, the standard proteasome is responsible for myofibrillar protein degradation while the immunoproteasome generates antigenic peptides for immune surveillance. The standard proteasome and immunoproteasome both increase in content and activity following catabolic conditions, such as aging and denervation. However, little is known about how the proteasome responds to stressful conditions that do not promote large perturbations in skeletal muscle proteolysis. Therefore, the purpose of this study was to assess proteasome content following a single session of acute muscular stress. METHODS: Male C57BL/6 wild type (WT) and immunoproteasome knockout lmp7−/−/mecl-1−/− (L7M1) mice ran on a motorized treadmill at a 22 degree decline for 70 min. Soleus muscles were then excised one and three days post-exercise and compared to muscle that did not exercise (baseline). Whole muscle ex vivo physiology, histology and biochemical analyses were used to assess the effects of immunoproteasome knockout and downhill running. TNF-α and MCP-1 levels were evaluated with ELISAs while immunoblots were used to quantify standard proteasome (19S, β1, β5) and immunoproteasome (11S, LMP7, MECL-1) content, and global levels of protein carbonylation. RESULTS: When compared to baseline, the bout of downhill running reduced twitch force one day post-exercise, indicative of low-frequency fatigue. However, it did not significantly depress tetanic force or alter the amount of TNF-α, MCP-1 or carbonylated proteins present in the muscle. Besides L7M1 muscle lacking LMP7 and MECL-1, no other differences in proteasome content were observed at baseline. In contrast, following the exercise, WT muscle tended to upregulate the catalytic subunits of the immunoproteasome while L7M1 muscle instead upregulated the catalytic subunits of the standard proteasome. CONCLUSIONS: Together, these results suggest that downhill running does not significantly alter tetanic force production or induce a large inflammatory response in mouse soleus muscle. Yet, it appears the stress of downhill running activates the production of specific subunits of the proteasome, of which are influenced by LMP7 and MECL-1.

A Rat Immobilization Model Based on Cage Volume Reduction: A Physiological Model for Bed Rest?

Bed rest has been an established treatment in the past prescribed for critically illness or convalescing patients, in order to preserve their body metabolic resource, to prevent serious complications and to support their rapid path to recovery. However, it has been reported that prolonged bed rest can have detrimental consequences that may delay or prevent the recovery from clinical illness. In order to study disuse-induced changes in muscle and bone, as observed during prolonged bed rest in humans, an innovative new model of muscle disuse for rodents is presented. Basically, the animals are confined to a reduced space designed to restrict their locomotion movements and allow them to drink and eat easily, without generating physical stress. The animals were immobilized for either 7, 14, or 28 days. The immobilization procedure induced a significant decrease of food intake, both at 14 and 28 days of immobilization. The reduced food intake was not a consequence of a stress condition induced by the model since plasma corticosterone levels –an indicator of a stress response– were not altered following the immobilization period. The animals showed a significant decrease in soleus muscle mass, grip force and cross-sectional area (a measure of fiber size), together with a decrease in bone mineral density. The present model may potentially serve to investigate the effects of bed-rest in pathological states characterized by a catabolic condition, such as diabetes or cancer.

Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size.

Muscle atrophy is a hallmark of cancer cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate-buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia.

Divergent regulation of insulin-like growth factor binding protein genes in cultured Atlantic salmon myotubes under different models of catabolism and anabolism

Much attention has been given to insulin-like growth factor (Igf) pathways that regulate the balance of skeletal muscle protein synthesis and breakdown in response to a range of extrinsic and intrinsic signals. However, we have a less complete understanding of how the same signals modulate muscle mass upstream of such signalling, through a family of functionally-diverse Igf-binding proteins (Igfbps) that modify the availability of Igfs to the cell receptor Igf1r. We exposed cultured myotubes from Atlantic salmon (Salmo salar L.) to treatments recapturing three catabolic signals: inflammation (interleukin-1β), stress (dexamethasone) and fasting (amino acid deprivation), plus one anabolic signal: recovery of muscle mass post-fasting (supplementation of fasted myotubes with Igf-I and amino acids). The intended phenotype of treatments was confirmed by significant changes in myotube diameter and immunofluorescent staining of structural proteins. We quantified the mRNA-level regulation of the full expressed Igf and Igfbp gene complement across a post-treatment time course, along with marker genes for muscle structural protein synthesis, as well as muscle breakdown, via the ubiquitin-proteasome and autophagy systems. Our results highlight complex, non-overlapping responses of Igfbp family members to the different treatments, suggesting that the profile of expressed Igfbps is differentially regulated by distinct signals promoting similar muscle remodelling phenotypes. We also demonstrate divergent regulation of salmonid-specific gene duplicates of igfbp5b1 and igfbp5b2 under distinct catabolic and anabolic conditions. Overall, this study increases our understanding of the regulation of Igfbp genes in response to signals that promote remodelling of skeletal muscle.

Effects of Insulin-Like Growth Factor-I on the Expression of Atrogin-1/MAFbx in Chick Myotube Cultures.

The expression of atrogin-1/MAFbx, a muscle-specific E3 ubiquitin ligase, is increased in catabolic conditions that result in muscle atrophy. The expression of atrogin-1/MAFbx mRNA is also decreased by the insulin-like growth factor-I (IGF-I) in mammalian skeletal muscle cell cultures. This study investigated the effect of IGF-I on the expression of atrogin-1/MAFbx in chicken skeletal muscle cell cultures. Chick myotubes were incubated with IGF-I for 1, 6, or 24 h. Protein content was increased by IGF-I (100 ng/ml) and incubated for 24 h in chick myotubes. The expression of atrogin-1/MAFbx mRNA decreased in the presence of IGF-I (1, 10, and 100 ng/ml) for 6 h in chick myotubes. The expression of the m-calpain large subunit and cathepsin B mRNA was not decreased by IGF-I. Phosphorylation of Akt and FOXO1 increased in the presence of IGF-I (100 ng/ml) for 1 h in chick myotubes. These results indicate that IGF-I suppresses atrogin-1/MAFbx mRNA expression by phosphorylation of Akt and FOXO1, resulting in an increase in muscle growth in chick myotube cultures.

Prevention of Burn-Induced Inflammatory Responses and Muscle Wasting by GTS-21, a Specific Agonist for α7 Nicotinic Acetylcholine Receptors.

Muscle wasting (MW) in catabolic conditions (e.g., burn injury [BI]) is a major risk factor affecting prognosis. Activation of interleukin-1β (IL-1β)/nuclear factor-kappa B (NF-κB), interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), and/or forkhead box O transcriptional factor (FOXO)-mediated gene transcription pathways is the pivotal trigger of inflammatory response-induced protein catabolic processes in muscle. The α7 acetylcholine receptors (α7AChRs) are upregulated in macrophages and peripheral tissues including skeletal muscle during MW conditions. Stimulation of α7AChRs mitigates inflammatory responses. Hypothesis tested is that attenuation of inflammation by α7AChR stimulation with specific α7AChR agonist, GTS-21, will reverse BI-induced body mass and MW by modulating inflammatory and proteolytic signals. Body surface area (30%) BI or sham BI mice were treated with GTS-21 or saline. Tibialis anterior (TA) muscle was harvested at 6 h, day 1 or 3 to examine inflammatory and proteolytic signals. GTS-21 significantly ameliorated the BI-induced increased expression of inflammatory cytokines IL-6, IL-1β, C-X-C motif chemokine ligand 2 (6 h), phosphorylated STAT3, and NF-κB (day 1) in TA muscle. GTS-21 also significantly inhibited BI-induced increase of MuRF1 and FOXO1 (day 1). Consistent with the cytokine and inflammatory mediator changes, BI-induced body weight and TA muscle mass loss at day 3 were mitigated by GTS-21 treatment. The beneficial effect of GTS-21 on BI changes was absent in methyllycaconitine (α7AChR antagonist)-treated wild-type and α7AChR knockout mice. GTS-21 stimulation of α7AChRs, by modulating multiple molecular signals related to inflammation and proteolysis, attenuates protein wasting, evidenced by maintenance of body weight and attenuation of distant muscle mass loss after BI. GTS-21 can be a novel, potent therapeutic option for reversal of BI-induced MW.

Sex Differences in Muscle Wasting.

With aging and other muscle wasting diseases, men and women undergo similar pathological changes in skeletal muscle: increased inflammation, enhanced oxidative stress, mitochondrial dysfunction, satellite cell senescence, elevated apoptosis and proteasome activity, and suppressed protein synthesis and myocyte regeneration. Decreased food intake and physical activity also indirectly contribute to muscle wasting. Sex hormones also play important roles in maintaining skeletal muscle homeostasis. Testosterone is a potent anabolic factor promoting muscle protein synthesis and muscular regeneration. Estrogens have a protective effect on skeletal muscle by attenuating inflammation; however, the mechanisms of estrogen action in skeletal muscle are less well characterized than those of testosterone. Age- and/or disease-induced alterations in sex hormones are major contributors to muscle wasting. Hence, men and women may respond differently to catabolic conditions because of their hormonal profiles. Here we review the similarities and differences between men and women with common wasting conditions including sarcopenia and cachexia due to cancer, end-stage renal disease/chronic kidney disease, liver disease, chronic heart failure, and chronic obstructive pulmonary disease based on the literature in clinical studies. In addition, the responses in men and women to the commonly used therapeutic agents and their efficacy to improve muscle mass and function are also reviewed.

Effect of acute and chronic autophagy deficiency on skeletal muscle apoptotic signaling, morphology, and function

Autophagy is a catabolic process that targets and degrades cytoplasmic materials. In skeletal muscle, autophagy is required for the control of mass under catabolic conditions, but is also basally active in the maintenance of myofiber homeostasis. In this study, we found that some specific autophagic markers (LC3-I, LC3-II, SQSTM1) were basally lower in glycolytic muscle compared to oxidative muscle of autophagy competent mice. In contrast, basal autophagic flux was higher in glycolytic muscle. In addition, we used several skeletal muscle-specific Atg7 transgenic mouse models to investigate the effect of acute (iAtg7−/−) and chronic (cAtg7−/−) autophagy deficiency on skeletal muscle morphology, contractility, and apoptotic signaling. While acute autophagy ablation (iAtg7−/−) resulted in increased centralized nuclei in glycolytic muscle, it did not alter contractile properties or measures of apoptosis and proteolysis. In contrast, with chronic autophagy deficiency (cAtg7−/−) there was an increased proportion of centralized nuclei, as well as reduced force and altered twitch kinetics in glycolytic muscle. Glycolytic muscle of cAtg7−/− mice also displayed an increased level of the pro-apoptotic protein BAX, as well as calpain and proteasomal enzymatic activity. Collectively, our data demonstrate cumulative damage from chronic skeletal muscle-specific autophagy deficiency with associated apoptotic and proteasomal upregulation. These findings point towards the importance of investigating different muscle/fiber types when studying skeletal muscle autophagy, and the critical role of autophagy in the maintenance of myofiber function, integrity, and cellular health.

FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension.

Muscle atrophy is a debilitating condition that affects a high percentage of the population with a negative impact on quality of life. Dissecting the molecular level of the atrophy process, and the similarities/dissimilarities among different catabolic conditions, is a necessary step for designing specific countermeasures to attenuate/prevent muscle loss. The FoxO family transcription factors represent one of the most important regulators of atrophy programme stimulating the expression of many atrophy-related genes. The findings of the present study clearly indicate that the signalling network controlling the atrophy programme is specific for each catabolic condition. Muscle atrophy is a complex process that is in common with many different catabolic diseases including disuse/inactivity and ageing. The signalling pathways that control the atrophy programme in the different disuse/inactivity conditions have not yet been completely dissected. The inhibition of FoxO is considered to only partially spare muscle mass after denervation. The present study aimed: (i) to determine the involvement of FoxOs in hindlimb suspension disuse model; (ii) to define whether the molecular events of protein breakdown are shared among different unloaded muscles; and finally (iii) to compare the data obtained in this model with another model of inactivity such as denervation. Both wild-type and muscle-specific FoxO1,3,4 knockout (FoxO1,3,4-/- ) mice were unloaded for 3 and 14days and muscles were characterized by functional, morphological, biochemical and molecular assays. The data obtained show that FoxOs are required for muscle loss and force drop during unloading. Moreover, we found that FoxO-dependent atrogenes vary in different unloaded muscles and that they diverge from denervation. The findings of the present study clearly indicate that the signalling network that controls the atrophy programme is specific for each catabolic condition.

Regulation of protein and mRNA expression of the mTORC1 repressor REDD1 in response to leucine and serum

Expression of the mTORC1 repressor, Regulated in DNA Damage and Development 1 (REDD1), is elevated in skeletal muscle during various catabolic conditions including fasting, hindlimb immobilization, and sepsis. Conversely, REDD1 expression is suppressed by anabolic stimuli such as resistance exercise or nutrient consumption following a fast. Though it is known that nutrient consumption reduces REDD1 expression, it is largely unknown how nutrients and hormones individually contribute to the reduction in REDD1 expression. Therefore, the purpose of the present study was to determine how nutrients and hormones individually regulate REDD1 expression. HeLa cells were deprived of leucine or serum for 10h, after which either leucine or serum was reintroduced to cell culture medium for 60min. Re-supplementation of either leucine or serum resulted in a reduction in REDD1 protein levels by 34.8±5.8% and 54.1±3.4%, respectively, compared to the deprived conditions. Re-supplementation of leucine or serum to deprived cells also led to a reduction in REDD1 mRNA content by 49.1±2.7% and 65.0±1.4%, respectively, compared to the deprived conditions. Interestingly, rates of REDD1 protein degradation were unaffected by either leucine or serum re-supplementation, as assessed in cells treated with cycloheximide to block protein synthesis. Likewise, addition of leucine- or serum to cells treated with Actinomycin D to inhibit gene transcription failed to alter the rate of REDD1 mRNA degradation. The data indicate that the leucine or serum-induced suppression of REDD1 expression occurs independent of changes in the rate of degradation of either the REDD1 protein or mRNA. Thus, the leucine- or serum-induced suppression likely occurs through alternative mechanism(s) such as reduced REDD1 gene transcription and/or mRNA translation.

The Suprachiasmatic Nucleus Modulates the Sensitivity of Arcuate Nucleus to Hypoglycemia in the Male Rat.

The suprachiasmatic nucleus (SCN) and arcuate nucleus (ARC) have reciprocal connections; catabolic metabolic information activates the ARC and inhibits SCN neuronal activity. Little is known about the influence of the SCN on the ARC. Here, we investigated whether the SCN modulated the sensitivity of the ARC to catabolic metabolic conditions. ARC neuronal activity, as determined by c-Fos immunoreactivity, was increased after a hypoglycemic stimulus by 2-deoxyglucose (2DG). The highest ARC neuronal activity after 2DG was found at the end of the light period (zeitgeber 11, ZT11) with a lower activity in the beginning of the light period (zeitgeber 2, ZT2), suggesting the involvement of the SCN. The higher activation of ARC neurons after 2DG at ZT11 was associated with higher 2DG induced blood glucose levels as compared with ZT2. Unilateral SCN-lesioned animals, gave a mainly ipsilateral activation of ARC neurons at the lesioned side, suggesting an inhibitory role of the SCN on ARC neurons. The 2DG-induced counterregulatory glucose response correlated with increased ARC neuronal activity and was significantly higher in unilateral SCN-lesioned animals. Finally, the ARC as site where 2DG may, at least partly, induce a counterregulatory response was confirmed by local microdialysis of 2DG. 2DG administration in the ARC produced a higher increase in circulating glucose compared with 2DG administration in surrounding areas such as the ventromedial nucleus of the hypothalamus (VMH). We conclude that the SCN uses neuronal pathways to the ARC to gate sensory metabolic information to the brain, regulating ARC glucose sensitivity and counterregulatory responses to hypoglycemic conditions.

Anabolic effects of leucine-rich whey protein, carbohydrate, and soy protein with and without β-hydroxy-β-methylbutyrate (HMB) during fasting-induced catabolism: A human randomized crossover trial

Protein-rich beverages are widely used clinically to preserve muscle protein and improve physical performance. Beverages with high contents of leucine or its keto-metabolite β-hydroxy-β-methylbutyrate (HMB) are especially anabolic in muscle, but it is uncertain whether this also applies to catabolic conditions such as fasting and whether common or separate intracellular signaling cascades are involved. To compare a specific leucine-rich whey protein beverage (LWH) with isocaloric carbohydrate- (CHO), soy protein (SOY), and soy protein+3g HMB (HMB) during fasting-induced catabolic conditions. Eight healthy lean male subjects underwent four interventions (LWH, CHO, SOY, and HMB) using a randomized crossover design. Each trial included a 36h fast and consisted of a 3h basal fasting period and a 4h 'sipping' period. Forearm net balances of phenylalanine (NBphe, measure of net protein loss) improved for all groups (p<0.05), but more prominently so for LWH and HMB compared with SOY (p<0.05). Muscle protein phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets eukaryotic translation factor 4E-binding protein 1 (4EBP1) and ribosomal S6 kinase 1 (S6) were distinctly increased during LWH consumption (p<0.05). The ratio between autophagy protein microtubule-associated protein 1 light chain-3β II and I (LC3II/LC3I, a measure of autophagy activity) was decreased during LWH and SOY intake compared with the fasting period (p<0.05). LWH and HMB have superior anabolic effects on muscle protein kinetics after 36h of fasting, and LWH distinctly activates the mTOR pathway. These novel findings suggest that leucine-rich whey protein and/or HMB are specifically beneficial during fasting-induced catabolic conditions.

The relationship of endogenous plasma concentrations of β-Hydroxy β-Methyl Butyrate (HMB) to age and total appendicular lean mass in humans

The maintenance of muscle mass and muscle strength is important for reducing the risk of chronic diseases. The age- related loss of muscle mass and strength is associated with adverse outcomes of physical disability, frailty and death. β-Hydroxy β-Methyl Butyrate (HMB), a metabolite of leucine, has beneficial effects on muscle mass and strength under various catabolic conditions. The objectives of the present study were to determine if age- related differences existed in endogenous plasma HMB levels, and to assess if HMB levels correlated to total appendicular lean mass and forearm grip strength. Anthropometry, dietary and physical activity assessment, and the estimation of fasting plasma HMB concentrations and handgrip strength were performed on the 305 subjects (children, young adults and older adults). Lean mass, which serves as a surrogate for muscle mass was measured using dual energy X-ray absorptiometry (DEXA). Mean plasma HMB concentrations were significantly lower with increasing age groups, with children having highest mean HMB concentration (p<0.01) followed by young adults and older adults. Female subjects (across all ages) had significantly lower plasma HMB concentrations. A significant positive correlation between HMB concentrations and appendicular lean mass normalized for body weight (%), appendicular lean mass (r=0.37; p<0.001) was observed in the young adults and older adults group. Handgrip strength was positively associated with plasma HMB concentrations in young adults (r=0.58; p<0.01) and the older adults group (r=0.28; p<0.01). The findings of the present study suggest that there is an age- related decline in endogenous HMB concentrations in humans and the HMB concentrations were positively correlated with appendicular lean mass and hand grip strength in young adults and older adults group.

Upregulation of MuRF1 and MAFbx participates to muscle wasting upon gentamicin-induced acute kidney injury

Acute Kidney Injury (AKI) is frequently encountered in hospitalized patients where it is associated with increased mortality and morbidity notably affecting muscle wasting. Increased protein degradation has been shown to be the main actor of AKI-induced muscle atrophy, but the proteolytic pathways involved are poorly known. The Ubiquitin Proteasome System (UPS) is almost systematically activated in various catabolic situations, and the E3 ligases MuRF1 and MAFbx are generally up regulated in atrophying muscles. We hypothesized that the UPS may be one of the main actors in catabolic skeletal muscles from AKI animals. We used gentamicin-induced acute kidney disease (G-AKI) in rats fed a high protein diet to promote acidosis. We first addressed the impact of G-AKI in the development of mild catabolic conditions. We found that both muscle atrophy and UPS activation were induced with the development of G-AKI. In addition, the phasic muscles were more sensitive to 7-days G-AKI (−11 to −17%, P<0.05) than the antigravity soleus muscle (−11%, NS), indicating a differential impact of AKI in the musculature. We observed an increased expression of the muscle-specific E3 ligases MuRF1 and MAFbx in phasic muscles that was highly correlated to the G-AKI severity (R2=0.64, P<0.01 and R2=0.71, P<0.005 respectively). Conversely, we observed no variation in the expression of three other E3 ligases (Nedd4, Trim32 and Fbxo30/MUSA1). Altogether, our data indicate that MuRF1 and MAFbx are sensitive markers and potential targets to prevent muscle atrophy during G-AKI.

EGR1 controls divergent cellular responses of distinctive nucleus pulposus cell types.

BackgroundImmediate early genes (IEGs) encode transcription factors which serve as first line response modules to altered conditions and mediate appropriate cell responses. The immediate early response gene EGR1 is involved in physiological adaptation of numerous different cell types. We have previously shown a role for EGR1 in controlling processes supporting chondrogenic differentiation. We recently established a unique set of phenotypically distinct cell lines from the human nucleus pulposus (NP). Extensive characterization showed that these NP cellular subtypes represented progenitor-like cell types and more functionally mature cells.MethodsTo further understanding of cellular heterogeneity in the NP, we analyzed the response of these cell subtypes to anabolic and catabolic factors. Here, we test the hypothesis that physiological responses of distinct NP cell types are mediated by EGR1 and reflect specification of cell function using an RNA interference-based experimental approach.ResultsWe show that distinct NP cell types rapidly induce EGR1 exposure to either growth factors or inflammatory cytokines. In addition, we show that mRNA profiles induced in response to anabolic or catabolic conditions are cell type specific: the more mature NP cell type produced a strong and more specialized transcriptional response to IL-1β than the NP progenitor cells and aspects of this response were controlled by EGR1.ConclusionsOur current findings provide important substantiation of differential functionality among NP cellular subtypes. Additionally, the data shows that early transcriptional programming initiated by EGR1 is essentially restrained by the cells’ epigenome as it was determined during development and differentiation. These studies begin to define functional distinctions among cells of the NP and will ultimately contribute to defining functional phenotypes within the adult intervertebral disc.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-016-0979-x) contains supplementary material, which is available to authorized users.

Insulin resistance is a two-sided mechanism acting under opposite catabolic and anabolic conditions

The survival of multi-cellular organisms depends on the organism ability to maintain glucose homeostasis for time of low/high nutrient availability or high energy needs, and the ability to fight infections or stress. These effects are realized through the insulin controlled transport of blood glucose into the insulin-responsive cells such as muscle, fat and liver cells. Reduction in the ability of these cells to take glucose from the blood in response to normal circulating levels of insulin is known as insulin resistance (IR). Chronic IR is a key pathological feature of obesity, type 2 diabetes, sepsis and cancer cachexia, however temporal IR are widely met in fasting/ hibernation, pregnancy, anti-bacterial immunity, exercise and stress. Paradoxically, a certain part of the IR-cases is associated with catabolic metabolism, whereas the other is related to anabolic pathways. How can this paradoxical IR-response be explained? What is the metabolic basis of this IR variability and its physiological and pathological impacts? An answer to these questions might be achieved through the hypothesis in which IR is considered as a two-sided mechanism acting under opposite metabolic conditions (catabolism and anabolism) but with the common aim to sustain glucose homeostasis in a wide metabolic range. To test this hypothesis, I examined the main metabolic distinctions between the varied IR-cases and their dependence on the blood glucose concentration, level of the IR-threshold, and catabolic/anabolic activation. On the basis of the established interrelations, a simple model of IR-distribution has been developed. The model revealed the «U-type distribution» form with separation into two main IR-groups, each determined in the catabolic or anabolic conditions with one exception – type 2 diabetes and its paradoxical catabolic activation in anabolic conditions. The dual opposing (or complementary) role for the IR opens a new possibility for better understanding the cause and consequences of transition from adaptive IR-responses to its pathological forms.

Mitochondrial Quality Control and Muscle Mass Maintenance.

Loss of muscle mass and force occurs in many diseases such as disuse/inactivity, diabetes, cancer, renal, and cardiac failure and in aging-sarcopenia. In these catabolic conditions the mitochondrial content, morphology and function are greatly affected. The changes of mitochondrial network influence the production of reactive oxygen species (ROS) that play an important role in muscle function. Moreover, dysfunctional mitochondria trigger catabolic signaling pathways which feed-forward to the nucleus to promote the activation of muscle atrophy. Exercise, on the other hand, improves mitochondrial function by activating mitochondrial biogenesis and mitophagy, possibly playing an important part in the beneficial effects of physical activity in several diseases. Optimized mitochondrial function is strictly maintained by the coordinated activation of different mitochondrial quality control pathways. In this review we outline the current knowledge linking mitochondria-dependent signaling pathways to muscle homeostasis in aging and disease and the resulting implications for the development of novel therapeutic approaches to prevent muscle loss.

Necessity of standardized protocol for platelet-rich plasma therapy in temporomandibular joint osteoarthritis.

Temporomandibular joint (TMJ) osteoarthritis (OA) is defined as chronic joint pain caused by the progressive degeneration of the articular cartilage through an imbalance between anabolic and catabolic conditions in the TMJ1. Although the pathophysiological etiologies of TMJ-OA are largely unknown, the excessive mechanical stress, aging processes involved with hormonal alterations, and individual heredity have been verified as risk factors for TMJ-OA. On the other hand, the increased risk factors induce a homeostatic imbalance between the anabolic (synthesis) and catabolic (degeneration) conditions in the articular cartilage of the TMJ. Subsequently, a homeostatic imbalance induces an upregulation of the pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 and catabolic growth factors in the synovial fluids of the TMJ2. Finally, upregulated pro-inflammatory cytokines and catabolic growth factors not only induce an increase in the cartilage degrading enzymes, such as matrix metalloproteinase (MMP)-13, MMP-3, MMP-1, a disintegrin, and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 to progressively breakdown of extracellular matrix3, but also induce the abnormal remodeling of the subchondral bone and the apoptosis of chondrocytes in the articular cartilage of TMJ. In addition, the biological linkage between the progressive degeneration of the articular cartilage of the TMJ and the occurrence of orofacial pain is still largely unknown. For these reasons, clinical treatments for patients with TMJ-OA focused only on the relief from orofacial pain caused by progressive degeneration of the articular cartilage. Therefore, as a strategy for maintaining the homeostasis of the synovial joints, recent studies on preventive medicine for OA attempted to shift the metabolic status of the joints from the catabolic to the anabolic state using anabolic materials. Platelet-rich plasma (PRP) is blood plasma that has been enriched with platelets and contains several different growth factors and cytokines that can stimulate the healing of various tissues. Therefore, autologous PRP has been considered a clinical anabolic material for patients with chronic joint pain caused by progressive cartilage degeneration of the synovial joints. A systematic review and meta-analysis related to the clinical efficacy of intra-articular PRP injection into the synovial joints with OA have shown significant clinical improvements4. More recently, Kutuk et al.5 and Hegab et al.6 reported that an intra-articular PRP injection is an effective treatment for TMJ-OA through the regeneration of fibrocartilage and cartilage, bone repair in the TMJ. On the other hand, Bottegoni et al.7 recently reported that the intra-articular PRP injection into the knee joint with moderate OA showed a decreased potential in elderly patients aged 80 years or over. This report indicates that the intra-articular PRP injection for patients with TMJ-OA can be performed in accordance with the physiological conditions and clinical diseases of patients. Because autologous PRP is prepared from the patient's own blood, the concentrated components of PRP differ according to the physiological conditions and clinical diseases of patients. For example, if PRP is prepared from a patient with autoimmune diseases, such as rheumatoid arthritis, it may have highly concentrated pro-inflammatory cytokines to accelerate the progressive cartilage degeneration of the TMJ. Therefore, it is important to standardize the clinical PRP preparation protocol for patients with TMJ-OA. Furthermore, standardized methods may include the number of platelets, timing and volume of PRP for injection according to the physiological conditions and clinical diseases of patients.

Lethal Hyperammonemia due to Ornithine Transcarbamylase Deficiency in a Patient with Severe Septic Shock

Severe hyperammonemia can occur as a result of inherited or acquired liver enzyme defects in the urea cycle, among which ornithine transcarbamylase deficiency (OTCD) is the most common form. We report a very rare case of a 45-year-old Korean male who was admitted to the intensive care unit (ICU) due to severe septic shock with acute respiratory failure caused by Pneumocystis jiroveci pneumonia. During his ICU stay with ventilator care, the patient suffered from marked hyperammonemia (>1,700 μg/dL) with abrupt mental change leading to life-threatening cerebral edema. Despite every effort including continuous renal replacement therapy and use of a molecular adsorbent recirculating system (extracorporeal liver support-albumin dialysis) to lower his serum ammonia level, the patient was not recovered. The lethal hyperammonemia in the patient was later proven to be a manifestation of acquired liver enzyme defect known as OTCD, which is triggered by serious catabolic conditions, such as severe septic shock with acute respiratory failure.