Myokine musclin alleviates lipid accumulation in 3T3-L1 adipocytes through PKA/p38-mediated upregulation of lipolysis and suppression of lipogenesis.

Musclin (MUS), an exercise-responsive myokine, has been documented to attenuate inflammation and enhance physical endurance. However, the effects of MUS on differentiation and related molecular mechanisms in adipocytes have not yet been studied. In this study, we found that treatment with MUS attenuated lipid accumulation in fully differentiated 3T3-L1 cells. Furthermore, MUS treatment enhanced lipolysis assessed by glycerol release, and caused apoptosis, whereas it reduced the expression of lipogenic proteins, such as PPARγ and processed SREBP1. Treatment with MUS augmented phosphorylated PKA expression, whereas suppressed p38 phosphorylation in 3T3-L1 adipocytes. H89, a selective PKA inhibitor reduced the effects of MUS on lipogenic lipid accumulation as well as lipolysis except for apoptosis. These results suggest that MUS promotes lipolysis and suppresses lipogenesis through a PKA/p38-dependent pathway, thereby ameliorating lipid deposition in cultured adipocytes. The current study offers the potential of MUS as a therapeutic approach for treating obesity with few side effects.

Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress.

Musclin, an exercise-responsive myokine, has the ability to attenuate inflammation, oxidative stress, and apoptosis in cardiomyocytes under pathogenic conditions. While the potential benefits of musclin in the cardiovascular system have been well documented, its effects on hepatic endoplasmic reticulum (ER) stress and lipid metabolism are not fully understood. The present study showed that musclin treatment reduced lipid accumulation and lipogenic protein expression in primary hepatocytes exposed to palmitate. Palmitate treatment led to an increase in markers of ER stress, which was reversed by musclin treatment. Musclin treatment increased SIRT7 expression and markers of autophagy in a dose-dependent manner. Small interfering (si) RNA of SIRT7 or 3-methyladenine (3 MA) reduced the effects of musclin on lipogenic lipid deposition in hepatocytes under hyperlipidemic conditions. These findings suggest that musclin can suppress palmitate-induced ER stress by upregulating SIRT7 and autophagy signaling, thereby alleviating lipid accumulation in primary hepatocytes. The current study provides a potential therapeutic strategy for the treatment of liver diseases characterized by lipid accumulation and ER stress, such as nonalcoholic fatty liver disease (NAFLD).

The correlation of serum musclin with diabetic nephropathy.

OBJECTIVE: Musclin is a recently found myokine involved in the process of glucose metabolism. The purpose of the present investigation is to evaluate the relationship between serum musclin levels and diabetic nephropathy (DN). METHODS: The current investigation included 175 (T2DM) cases and 62 controls. T2DM patients were divided into three subgroups: normoalbuminuria (DN0), microalbuminuria (DN1), and macroalbuminuria (DN2) on the basis of the values of urine albumin to creatinine ratio (ACR). RESULTS: T2DM group displayed higher serum musclin than the controls. Serum musclin were remarkably elevated in DN2 subgroup compared with DN0 and DN1 subgroups. In addition, elevated serum musclin was observed in DN1 subgroup than in the DN0 subgroup. Serum musclin was correlated with an increased risk of having T2DM and DN using a logistic regression model. Linear regression analysis showed that serum musclin was negatively related with gender, and positively related with body mass index, systolic blood pressure, blood urea nitrogen, creatinine, and ACR. CONCLUSION: Serum musclin increases with the progressed stages of DN. Serum musclin is associated with renal function parameters and ACR.

Evaluation of pea/rice and amylopectin/chromium as an alternative protein source to improve muscle protein synthesis in rats.

BACKGROUND: A preclinical study reported that the combination of an amylopectin/chromium complex (ACr) of branched-chain amino acids (BCAA) significantly enhanced muscle protein synthesis (MPS). This study was conducted to determine the effects of the addition of ACr complex to a pea/rice (PR) protein on MPS, insulin, muslin levels, and the mTOR pathway in exercised rats. METHODS: Twenty-four rats were divided into three groups: (i) exercise (Ex); (ii) Ex + PR 1:1 blend (0.465 g/kg BW); (iii) Ex + PR + ACr (0.155 g/kg BW). On the day of single-dose administration, after the animals were exercised at 26/m/min for 2 h, the supplement was given by oral gavage. The rats were injected with a bolus dose (250 mg/kg BW, 25 g/L) of deuterium-labeled phenylalanine to determine the protein fractional synthesis rate (FSR) one h after consuming the study product. RESULTS: The combination of PR and ACr enhanced MPS by 42.55% compared to the Ex group, while Ex + PR alone increased MPS by 30.2% over the Ex group (p < 0.0001) in exercised rats. Ex + PR plus ACr significantly enhanced phosphorylation of mTOR and S6K1 (p < 0.0001), and 4E-BP1 (p < 0.001) compared to the Ex (p < 0.0001). PR to ACr also significantly increased insulin and musclin levels (p < 0.0001) in exercised rats. Additionally, compared to Ex + PR alone, Ex + PR + ACr enhanced mTOR (p < 0.0001) and S6K1 (p < 0.0001) levels. CONCLUSION: These data suggested that PR + ACr may provide an alternative to animal proteins for remodeling and repairing muscle by stimulating MPS and mTOR signaling pathways in post-exercised rats. More preclinical and clinical human studies on combining pea/rice and amylopectin/chromium complex are required.

Myokine Musclin Is Critical for Exercise-Induced Cardiac Conditioning.

This study investigates the role and mechanisms by which the myokine musclin promotes exercise-induced cardiac conditioning. Exercise is one of the most powerful triggers of cardiac conditioning with proven benefits for healthy and diseased hearts. There is an emerging understanding that muscles produce and secrete myokines, which mediate local and systemic "crosstalk" to promote exercise tolerance and overall health, including cardiac conditioning. The myokine musclin, highly conserved across animal species, has been shown to be upregulated in response to physical activity. However, musclin effects on exercise-induced cardiac conditioning are not established. Following completion of a treadmill exercise protocol, wild type (WT) mice and mice with disruption of the musclin-encoding gene, Ostn, had their hearts extracted and exposed to an ex vivo ischemia-reperfusion protocol or biochemical studies. Disruption of musclin signaling abolished the ability of exercise to mitigate cardiac ischemic injury. This impaired cardioprotection was associated with reduced mitochondrial content and function linked to blunted cyclic guanosine monophosphate (cGMP) signaling. Genetic deletion of musclin reduced the nuclear abundance of protein kinase G (PKGI) and cyclic adenosine monophosphate (cAMP) response element binding (CREB), resulting in suppression of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and its downstream targets in response to physical activity. Synthetic musclin peptide pharmacokinetic parameters were defined and used to calculate the infusion rate necessary to maintain its plasma level comparable to that observed after exercise. This infusion was found to reproduce the cardioprotective benefits of exercise in sedentary WT and Ostn-KO mice. Musclin is essential for exercise-induced cardiac protection. Boosting musclin signaling might serve as a novel therapeutic strategy for cardioprotection.

Efficacy of high-intensity interval- or continuous aerobic-training on insulin resistance and muscle function in adults with metabolic syndrome: a clinical trial.

PURPOSE: We carried out a randomized, clinical trial in adults of both sexes with metabolic syndrome (MS) to assess the efficacy of high-intensity, low-volume interval training (HIIT) compared to moderate-intensity continuous training (MICT) on insulin resistance (IR), muscle mass, muscle activation, and serum musclin. METHODS: Fasting glycemia, insulinemia, and glycated haemoglobin were determined by conventional methods, IR by Homeostatic model assessment (HOMA), lean mass by Dual-Energy X-ray Absorptiometry, muscle activation through carnosine by Proton Magnetic Resonance Spectroscopy, and musclin by Enzyme-Linked ImmunoSorbent Assay before and after a supervised, three-times/week, 12-week treadmill programme. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). MICT (n = 31) trained at 60% of VO2peak for 30 min. RESULTS: Patients had a mean age of 50.8 ± 6.0 years, body mass index of 30.6 ± 4.0 kg/m2, and VO2peak of 29.0 ± 6.3 mL.kg-1.min-1. Compared to MICT, HIIT was not superior at reducing Ln HOMA-IR (adjusted mean difference: 0.083 [95%CI - 0.092 to 0.257]), carnosine or musclin or at increasing thigh lean mass. HIIT increased carnosine by 0.66 mmol/kg.ww (95% CI 0.08-1.24) after intervention. Both interventions reduced IR, body fat percentage and increased total lean mass/height2 and VO2peak. Musclin showed a non-significant reduction with a small effect size after both interventions. CONCLUSION: Compared to MICT, HIIT is not superior at reducing IR, carnosine or musclin or at increasing skeletal muscle mass in adults with MS. Both training types improved IR, muscle mass and body composition. NCT03087721, March 22nd, 2017. TRIAL REGISTRATION NUMBER: NCT03087721. Registered March 22nd, 2017.

Role of Cardiac Natriuretic Peptides in Heart Structure and Function.

Cardiac natriuretic peptides (NPs), atrial NP (ANP) and B-type NP (BNP) are true hormones produced and released by cardiomyocytes, exerting several systemic effects. Together with C-type NP (CNP), mainly expressed by endothelial cells, they also exert several paracrine and autocrine activities on the heart itself, contributing to cardiovascular (CV) health. In addition to their natriuretic, vasorelaxant, metabolic and antiproliferative systemic properties, NPs prevent cardiac hypertrophy, fibrosis, arrhythmias and cardiomyopathies, counteracting the development and progression of heart failure (HF). Moreover, recent studies revealed that a protein structurally similar to NPs mainly produced by skeletal muscles and osteoblasts called musclin/osteocrin is able to interact with the NPs clearance receptor, attenuating cardiac dysfunction and myocardial fibrosis and promoting heart protection during pathological overload. This narrative review is focused on the direct activities of this molecule family on the heart, reporting both experimental and human studies that are clinically relevant for physicians.

Cardioprotective effects of high-intensity interval training are mediated through microRNA regulation of mitochondrial and oxidative stress pathways.

Human studies have shown high-intensity interval training (HIIT) has beneficial cardiovascular effects and is typically more time-efficient compared with traditional endurance exercise. The main goal of this study is to show the potential molecular and functional cardiovascular benefits of HIIT compared with endurance training (ET). Three groups of mice were used including sedentary-control, ET mice, and HIIT mice groups. Results indicated ejection fraction was increased in HIIT compared with ET while fractional shortening was increased in the HIIT group compared with both groups. Blood flow of the abdominal aorta was increased in both exercise groups compared with control. Increases in cross-sectional area and mitochondrial and antioxidative markers in HIIT compared with control were observed, along with several microRNAs. These findings indicate HIIT has specific cardiac-protective effects and may be a viable alternative to traditional ET as a cardiovascular preventative medicine intervention.

C/EBPß mediates palmitate-induced musclin expression via the regulation of PERK/ATF4 pathways in myotubes.

Musclin is a muscle-secreted cytokine that disrupts glucose uptake and glycogen synthesis in type 2 diabetes. The purpose of this study was to investigate the mechanisms responsible for the regulation of musclin gene expression in response to treatment with palmitate. RNA sequencing results showed that biological processes activated by palmitate are mainly enriched in endoplasmic reticulum (ER) stress. The protein kinase RNA-like ER kinase (PERK) signaling pathway is involved in the regulation of musclin expression induced by palmitate. Chromatin immunoprecipitation data showed that activating transcription factor 4 (ATF4)-downstream of PERK-bound to the promoter of the C/EBPß gene. Notably, C/EBPß also contains a binding site in the region -94~-52 of the musclin gene promoter. Knockdown or knockout of PERK and ATF4 using short hairpin RNA or CRISPR-Cas9 decreased the expression of C/EBPß and musclin induced by palmitate. Furthermore, knockdown and knockout of C/EBPß alleviated the high expression of musclin in response to treatment with palmitate. Moreover, CRISPR-Cas9 knockout of the region -94~-52 in which C/EBPß binds to the promoter of musclin abrogated the induction of high musclin expression caused by palmitate. Collectively, these findings suggest that treatment with palmitate activates the PERK/ATF4 signaling pathway, which in turn increases the expression of C/EBPß. C/EBPß binds directly to the promoter of the musclin gene and upregulates its expression.

A potent and selective natriuretic peptide receptor-3 blocker 11-mer peptide created by hybridization of musclin and atrial natriuretic peptide.

The natriuretic peptide (NP) system is a critical endocrine, autocrine, and paracrine system and has been investigated for potential use against cardiovascular and metabolic diseases. The clearance of NPs is regulated by the proteolysis of neutral endopeptidase (NEP) and by endocytosis via natriuretic peptide receptor-3 (NPR3). A linear NPR3-selective peptide, [Cha8]-ANP(7-16)-NH2 (1), showed potent binding affinity for NPR3 but poor predicted chemical stability due to its free thiol group. A 12-mer peptide (9) without a thiol group was designed by the hybridization of two NPR3-binding peptides: a linear ANP fragment peptide analog and musclin, a murine member of the bHLH family of transcription factors, possessed high binding affinity and strict selectivity for NPR3. To increase the proteolytic resistance of 9, amino acid substitutions at the cleavage sites led to hydroxyacetyl-[d-Phe5,d-Hyp7,Cha8,d-Ser9,Hyp11,Arg(Me)14]-ANP(5-15)-NHCH3 (23), showing high and selective binding affinity for NPR3 over NPR1 and excellent stability in mouse serum. Compound 23 increased intracellular cGMP concentrations in primary cultured adipocytes, and continuous administration induced substantial plasma cGMP elevation in mice, suggesting its potential to clarify the physiological role of NPR3 and its therapeutic application.

Palmitate increases musclin gene expression through activation of PERK signaling pathway in C2C12 myotubes.

Musclin is a type of muscle-secreted cytokine and its increased gene expression induces insulin resistance in type 2 diabetes. However, the mechanism underlying increased musclin gene expression is currently unclear. Excessive saturated fatty acids (SFA) can activate the secretion of several muscle-secreted cytokines as well as endoplasmic reticulum (ER) stress pathway, thereby contributing to the development of type 2 diabetes. The purpose of this study was to investigate the mechanisms responsible for the effect of palmitate, the most abundant SFA in the plasma, on the gene expression of musclin in C2C12 myotubes. Treatment of C2C12 myotubes with palmitate or tunicamycin significantly increased the expression of musclin as well as ER stress-related genes, but treatment with oleate did not. Pre-treatment of C2C12 myotubes with 4-phenyl butyrate suppressed the expression of ER stress-related genes, simultaneously, resulting in decreased expression of the musclin gene induced by palmitate or tunicamycin. These results indicate that ER stress is related to palmitate-induced musclin gene expression. Moreover, palmitate-induced musclin gene expression was significantly inhibited in C2C12 myotubes when PERK pathway signaling was suppressed by knockdown of the PERK gene or treatment with GSK2656157, a PERK autophosphorylation inhibitor. However, there was no difference in the palmitate-induced musclin gene expression when IRE1 and ATF6 signaling pathways were suppressed by knockdown of the IRE1 and ATF6 genes. These findings suggest that palmitate increases musclin gene expression via the activation of the PERK signaling pathway in C2C12 myotubes.

Musclin Mitigates the Attachment of HUVECs to THP-1 Monocytes in Hyperlipidemic Conditions through PPARα/HO-1-Mediated Attenuation of Inflammation.

Musclin, a myokine, undergoes modulation during exercise and has demonstrated anti-inflammatory effects in cardiomyocytes and glomeruli. However, its role in atherosclerotic responses remains unclear. This study aimed to explore the impact of musclin on inflammatory responses and the interaction between endothelial cells and monocytes under hyperlipidemic conditions. The attachment levels of THP-1 monocytes on cultured HUVECs were examined. Inflammation and the expression of cell adhesion molecules were also evaluated. To explore the molecular mechanisms of musclin, PPARα or heme oxygenase 1 (HO-1) siRNA transfection was performed in HUVECs. The results revealed that treatment with recombinant musclin effectively suppressed the attachment of palmitate-induced HUVECs to THP-1 cells and reduced the expression of cell adhesion proteins (ICAM-1, VCAM-1, and E-selectin) in HUVECs. Furthermore, musclin treatment ameliorated the expression of inflammation markers (phosphorylated NFκB and IκB) in both HUVECs and THP-1 monocytes, as well as the release of TNFα and MCP-1 from HUVECs and THP-1 monocytes. Notably, musclin treatment augmented the expression levels of PPARα and HO-1. However, when PPARα or HO-1 siRNA was employed, the beneficial effects of musclin on inflammation, cell attachment, and adhesion molecule expression were abolished. These findings indicate that musclin exerts anti-inflammatory effects via the PPARα/HO-1 pathway, thereby mitigating the interaction between endothelial cells and monocytes. This study provides evidence supporting the important role of musclin in ameliorating obesity-related arteriosclerosis and highlights its potential as a therapeutic agent for treating arteriosclerosis.

Exercise-induced Musclin determines the fate of fibro-adipogenic progenitors to control muscle homeostasis.

The effects of exercise on fibro-adipogenic progenitors (FAPs) are unclear, and the direct molecular link is still unknown. In this study, we reveal that exercise reduces the frequency of FAPs and attenuates collagen deposition and adipose formation in injured or disused muscles through Musclin. Mechanistically, Musclin inhibits FAP proliferation and promotes apoptosis in FAPs by upregulating FILIP1L. Chromatin immunoprecipitation (ChIP)-qPCR confirms that FoxO3a is the transcription factor of FILIP1L. In addition, the Musclin/FILIP1L pathway facilitates the phagocytosis of apoptotic FAPs by macrophages through downregulating the expression of CD47. Genetic ablation of FILIP1L in FAPs abolishes the effects of exercise or Musclin on FAPs and the benefits on the reduction of fibrosis and fatty infiltration. Overall, exercise forms a microenvironment of myokines in muscle and prevents the abnormal accumulation of FAPs in a Musclin/FILIP1L-dependent manner. The administration of exogenous Musclin exerts a therapeutic effect, demonstrating a potential therapeutic approach for muscle atrophy or acute muscle injury.

Dynamic Response of Musclin, a Myokine, to Aerobic Exercise and Its Interplay with Natriuretic Peptides and Receptor C.

OBJECTIVES: Musclin, recently identified as a myokine, has been recognized for its physiological significance in potentiating the functional properties of natrieutic peptides (NPs) through competitive inhibition of their clearance receptor, natrieutic peptide receptor C (NPR-C). This study, for the first time in the literature, investigated the dynamic response of musclin during and after aerobic exercise in humans, exploring its potential as a myokine and its interaction with NPs and NPR-C in the context of exercise-induced metabolic responses. METHODS: Twenty-one inactive young males participated, and we assessed changes in serum levels of musclin, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), epinephrine (Epi), and glycerol as an indicative of lipid mobilization, during and after moderate-intensity aerobic exercise. Furthermore, we evaluated the gene expression of NPR-C in subcutaneous fat biopsies. RESULTS: Serum musclin levels increased significantly during aerobic exercise, followed by a decline during recovery, remaining elevated compared to baseline. Significant correlations were found between musclin responses and lean body mass (LBM), indicating its regulation by skeletal muscle mass and exercise. Exercise-induced changes in musclin positively correlated with those of ANP, potentially preventing ANP degradation. Additionally, a potential interplay between NPR-C expression and musclin dynamics on ANP was suggested. However, musclin's influence on lipid mobilization was not predominant when considering other lipolytic factors during exercise. DISCUSSION: Musclin's classification as a myokine is supported by its response to aerobic exercise and its association with LBM. Additionally, its interactions with NPR-C and NPs suggest its physiological relevance and potential clinical implications.

Decreased serum musclin concentration is independently associated with the high prevalence of sarcopenia in Chinese middle-elderly patients with type 2 diabetes mellitus.

INTRODUCTION AND AIMS: Sarcopenia is a complication of diabetes mellitus, which can increase hospitalization and lead to poor outcomes. The present study investigated the relationship between the serum musclin concentration and the sarcopenia morbidity in Chinese middle-elderly patients with type 2 diabetes mellitus. METHODS: We recruited 220 patients with type 2 diabetes mellitus, all of whom completed gait speed, handgrip strength tests, and whole-body dual-energy x-ray measurements to calculate the appendicular skeletal muscle mass index (ASMI). The patients were divided into sarcopenia (n = 110) and non-sarcopenia groups (n = 110). The serum musclin concentration was measured using an enzyme-linked immunosorbent assay. RESULTS: The serum musclin concentration was significantly lower in the sarcopenia group (712.82 pg/mL) than in the non-sarcopenia group (922.53 pg/mL). The serum musclin concentration positively correlated with the whole-body skeletal mass (r = 0.230; P = 0.001). Sarcopenia morbidity declined as the quartile of serum musclin concentration increased (P = 0.001), and a negative correlation was observed between the serum musclin concentration and the prevalence of sarcopenia (odds ratio = 0.998, P = 0.001). The correlation remained when quartiles were considered. CONCLUSIONS: The serum musclin concentration is an independent protective factor for sarcopenia in Chinese middle-elderly patients with type 2 diabetes mellitus.

Musclin prevents depression-like behavior in male mice by activating urocortin 2 signaling in the hypothalamus.

Introduction: Physical activity is recommended as an alternative treatment for depression. Myokines, which are secreted from skeletal muscles during physical activity, play an important role in the skeletal muscle-brain axis. Musclin, a newly discovered myokine, exerts physical endurance, however, the effects of musclin on emotional behaviors, such as depression, have not been evaluated. This study aimed to access the anti-depressive effect of musclin and clarify the connection between depression-like behavior and hypothalamic neuropeptides in mice. Methods: We measured the immobility time in the forced swim (FS) test, the time spent in open arm in the elevated-plus maze (EPM) test, the mRNA levels of hypothalamic neuropeptides, and enumerated the c-Fos-positive cells in the paraventricular nucleus (PVN), arcuate nucleus (ARC), and nucleus tractus solitarii (NTS) in mice with the intraperitoneal (i.p.) administration of musclin. Next, we evaluated the effects of a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist, selective CRF type 2 receptor antagonist, melanocortin receptor (MCR) agonist, and selective melanocortin 4 receptor (MC4R) agonist on changes in behaviors induced by musclin. Finally we evaluated the antidepressant effect of musclin using mice exposed to repeated water immersion (WI) stress. Results: We found that the i.p. and i.c.v. administration of musclin decreased the immobility time and relative time in the open arms (open %) in mice and increased urocortin 2 (Ucn 2) levels but decreased proopiomelanocortin levels in the hypothalamus. The numbers of c-Fos-positive cells were increased in the PVN and NTS but decreased in the ARC of mice with i.p. administration of musclin. The c-Fos-positive cells in the PVN were also found to be Ucn 2-positive. The antidepressant and anxiogenic effects of musclin were blocked by central administration of a CRF type 2 receptor antagonist and a melanocortin 4 receptor agonist, respectively. Peripheral administration of musclin also prevented depression-like behavior and the decrease in levels of hypothalamic Ucn 2 induced by repeated WI stress. Discussion: These data identify the antidepressant effects of musclin through the activation of central Ucn 2 signaling and suggest that musclin and Ucn 2 can be new therapeutic targets and endogenous peptides mediating the muscle-brain axis.

Low Circulating Musclin is Associated With Adverse Prognosis in Patients Undergoing Transcatheter Aortic Valve Implantation at Low-Intermediate Risk.

Background Musclin is an activity-stimulated and cardioprotective myokine that attenuates pathological cardiac remodeling. Musclin deficiency, in turn, results in reduced physical endurance. The aim of this study was to assess the prognostic value of circulating musclin as a novel, putative biomarker to identify patients undergoing transcatheter aortic valve implantation (TAVI) who are at a higher risk of death. Methods and Results In this study, we measured systemic musclin levels in 368 patients undergoing TAVI who were at low to intermediate clinical risk (median EuroSCORE [European System for Cardiac Operative Risk Evaluation] II: 3.5; quartile 1-quartile, 2.2%-5.3%), whereby 209 (56.8%) patients were at low and 159 (43.2%) were at intermediate risk. Median preprocedural musclin levels were 2.7 ng/mL (quartile 1-quartile 3, 1.5-4.6 ng/mL). Musclin levels were dichotomized in low (<2.862 ng/mL, n=199 [54.1%]) or high (≥ 2.862 ng/mL, n=169 [45.9%]) groups using cutoff values determined by classification and regression tree analysis. The primary end point was 1-year overall survival. Patients with low circulating musclin levels exhibited a significantly higher prevalence of frailty, low albumin values, hypertension, and history of stroke as well as higher N-terminal pro-B-type natriuretic peptide. Low musclin levels significantly predicted risk of death in univariable (hazard ratio, 1.81; 95% CI, 1.00-3.53 [P=0.049]) and multivariable (adjusted hazard ratio, 2.45; 95% CI, 1.06-5.69 [P=0.037]) Cox regression analyses. Additionally, low musclin levels in combination with conventional EuroSCORE II suggested improved risk stratification in patients undergoing TAVI who were at low to intermediate clinical risk into subgroups with reduced 1-year survival rates by log-rank test (P for trend=0.003). Conclusions Circulating musclin is an independent predictor of 1-year overall survival in patients undergoing TAVI. Combined with EuroSCORE II, circulating musclin might help to improve prediction of mortality in patients undergoing TAVI who are at low to intermediate clinical risk.

Decreased muscle-derived musclin by chronic resistance exercise is associated with improved insulin resistance in rats with type 2 diabetes.

Chronic resistance exercise induces improved hyperglycemia in patients with type 2 diabetes mellitus. Musclin, a muscle-derived secretory factor, is involved in the induction of insulin resistance via the downregulation of the glucose transporter-4 (GLUT-4) signaling pathway in skeletal muscles. However, whether musclin affects the mechanism of resistance exercise remains unclear. This study aimed to clarify whether decreased muscle-derived musclin secretion in chronic resistance exercise is involved in the improvement of insulin resistance via the GLUT-4 signaling pathway in rats with type 2 diabetes. Male, 20-week-old, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetes model, were randomly divided into two groups: sedentary control (OLETF-Con) and chronic resistance exercise (OLETF-RT; climbing a ladder three times a week on alternate days for 8 weeks), whereas Long-Evans Tokushima Otsuka rats were used as the nondiabetic sedentary control group. OLETF-Con rats showed increased fasting glucose levels, decreased insulin sensitivity index (QUICKI), muscle GLUT-4 translocation, and protein kinase B (Akt) phosphorylation, and concomitantly increased muscle musclin expression. In contrast, OLETF-RT rats significantly reduced muscle musclin expression, improved hyperglycemia, and QUICKI through an accelerated muscle GLUT-4/Akt signaling pathway. Moreover, chronic resistance exercise-induced reduction of muscle musclin was correlated with changes in fasting glucose, QUICKI, GLUT-4 translocation, and Akt phosphorylation. These findings suggest that the reduction in muscle-derived musclin production by chronic resistance exercise may be involved in improved insulin resistance in rats with type 2 diabetes.

Decreased plasma musclin levels are associated with potential atrial fibrillation in non-diabetic patients.

BACKGROUND: Musclin is involved in the regulation of natriuretic peptide (NP) clearance and may affect the concentration of atrial natriuretic peptide (ANP). It has also been found to play an important role in several diseases, such as diabetes mellitus and hypertension. Both abnormalities in ANP and associated medical history are involved in the pathogenesis of atrial fibrillation (AF). However, plasma concentration of musclin as a biomarker for risk stratification in patients with AF has not been fully investigated. METHODS: Plasma musclin levels were measured in 290 patients with AF (including 199 paroxysmal AF patients and 91 persistent AF patients) and 120 control subjects. The association between plasma musclin levels and AF onset, as well as its predictive effects on clinical outcomes after cryoballoon ablation were analyzed. RESULTS: AF patients were found to have a lower concentration of plasma musclin than healthy controls. Moreover, in the non-diabetic group and normal N-terminal pro-brain natriuretic peptide (NT-proBNP) level group, the association between lower plasma concentration of musclin and AF remained significant. According to receiver operating characteristic (ROC) curve analysis, the optimal cut-off point of musclin for predicting AF onset was 54.94 ng/mL, which had a sensitivity of 81.67% and a specificity of 31.47% [area under the ROC curve (AUC) =60.71%]. In follow-up studies, both diabetes and left atrial size were independent predictors of AF recurrence after ablation, while musclin showed only a modest relationship with the outcome of cryoballoon ablation. CONCLUSIONS: Our data indicated that decreased musclin was associated with the onset of AF. Moreover, lower plasma levels of musclin were an independent risk factor of AF in non-diabetic patients. Our studies suggest that musclin could be a predictive factor for the onset of AF.