FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT-1/PGC-α pathway.

Obesity is associated with biological dysfunction in skeletal muscle. As a condition of obesity accompanied by muscle mass loss and physical dysfunction, sarcopenic obesity (SO) has become a novel public health problem. Human fibroblast growth factor 19 (FGF19) plays a therapeutic role in metabolic diseases. However, the protective effects of FGF19 on skeletal muscle in obesity and SO are still not completely understood. Our results showed that FGF19 administration improved muscle loss and grip strength in young and aged mice fed a high-fat diet (HFD). Increases in muscle atrophy markers (FOXO-3, Atrogin-1, MuRF-1) were abrogated by FGF19 in palmitic acid (PA)-treated C2C12 myotubes and in the skeletal muscle of HFD-fed mice. FGF19 not only reduced HFD-induced body weight gain, excessive lipid accumulation and hyperlipidaemia but also promoted energy expenditure (PGC-1α, UCP-1, PPAR-γ) in brown adipose tissue (BAT). FGF19 treatment restored PA- and HFD-induced hyperglycaemia, impaired glucose tolerance and insulin resistance (IRS-1, GLUT-4) and mitigated the PA- and HFD-induced decrease in FNDC-5/irisin expression. However, these beneficial effects of FGF19 on skeletal muscle were abolished by inhibiting AMPK, SIRT-1 and PGC-1α expression. Taken together, this study suggests that FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin secretion partially through the AMPK/SIRT-1/PGC-α signalling pathway, which might be a potential therapeutic target for obesity and SO.

Inhibition of soluble epoxide hydrolase (sEH) protects hippocampal neurons and reduces cognitive decline in type 2 diabetic mice.

Diabetes mellitus is a metabolic disorder that can lead to cognitive dysfunction. The hippocampus plays an important role in the cognitive function. Research has identified correlations between hippocampal impairment and diabetes, yet their intermediate remains unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects by suppressing inflammation, apoptosis and oxidative stress. In this study, under diabetic conditions both hippocampal injury and cognitive decline are accompanied by upregulation of sEH. Moreover, the sEH inhibitor trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) prevents cognitive dysfunction and decreased ROS accumulation and apoptosis in the diabetic hippocampus. t-AUCB treatment restored neuronal synaptic plasticity by restoring the expression of the postsynaptic proteins Postsynaptic density protein-95 (PSD95) and N-methyl-d-aspartate receptor subunit 2B (NR2B), the levels of which were positively correlated with Proline-rich tyrosine kinase 2 (Pyk2) levels under diabetic conditions. Thus, we suggest that hippocampal protection via sEH inhibition might be a potential therapeutic approach to attenuate the progression of cognitive decline in diabetes.

Effect of sarcolipin-mediated cell transdifferentiation in sarcopenia-associated skeletal muscle fibrosis.

Fibrosis is a key pathological event during muscle aging that accelerates the development of sarcopenia. We show that sarcolipin (SLN) is highly expressed during aging, promotes intracellular calcium overload and participates in impaired myogenic differentiation. d-Galactose (D-gal) was used to induce senescence in C2C12 myoblasts. Conventional AAV-mediated SLN knockdown cells were used to study the role of SLN in muscle physiology and pathophysiology. C2C12 cells were treated with D-gal, which promoted fibrosis and SLN upregulation. The expression of TGF-ß1 and α-SMA, which participate in myogenic transdifferentiation, were also elevated. C2C12 cells with reduced sarcolipin expression produced decreased amounts of collagen. Our study identified an unrecognized role of SLN in regulating myogenic transdifferentiation during aging-associated skeletal muscle cell fibrosis. Targeting SLN may be a novel therapeutic strategy to relieve sarcopenia-associated muscle fibrosis.

Soluble epoxide hydrolase inhibitor protects against blood-brain barrier dysfunction in a mouse model of type 2 diabetes via the AMPK/HO-1 pathway.

Diabetes mellitus is a metabolic disorder that can lead to blood-brain barrier (BBB) disruption and cognitive decline. However, the mechanisms of BBB breakdown in diabetes are still unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects on vascular structure and functions. In the current study, we showed increased vascular permeability of the BBB, which was accompanied by upregulation of sEH and downregulation of 14,15-EET. Moreover, the sEH inhibitor t-AUCB restored diabetic BBB integrity in vivo, and 14,15-EET prevented ROS accumulation and MEC injury in vitro. t-AUCB or 14,15-EET treatment provoked AMPK/HO-1 activation under diabetic conditions in vivo and in vitro. Thus, we suggest that decreased EET degradation by sEH inhibition might be a potential therapeutic approach to attenuate the progression of BBB injury in diabetic mice via AMPK/HO-1 pathway activation.

Study on the Degradation Effect of Carbonaceous Shale under the Coupling Effect of Chemical Erosion and High Temperature.

The southwest region of China has abundant groundwater and high-temperature geothermal energy. Carbonaceous shale, as one of the typical surrounding rocks in this region, often suffers from deterioration effects due to the coupled action of groundwater chemical erosion and high temperature, which affects the long-term stability of tunnel engineering. In order to investigate the deterioration effects of carbonaceous shale under the coupled action of chemical erosion and high temperature, carbonaceous shale from a tunnel of Lixiang Railway in Yunnan Province was taken as the research object. The microstructure and mineral composition of the samples before and after chemical erosion were obtained with a scanning electron microscope-energy dispersive spectrometer and an X-ray diffraction test. Then, triaxial compression tests were conducted on the samples under different time points and different temperature effects of chemical erosion, and the stress-strain curves and the deterioration laws under a single factor were obtained. An improved numerical simulation method based on the parallel bond model was developed, which can account for the coupled effects of chemical erosion and high temperature on the rock. By simulating the triaxial compression test of carbonaceous shale, the deterioration law of carbonaceous shale under the coupled action was discussed. The results show that chemical erosion has a significant deterioration effect on the triaxial compressive strength of carbonaceous shale, and the degree of deterioration is related to the erosion time. In the first 30 days of erosion, the triaxial compressive strength of carbonaceous shale decreased by 11.38%, which was the largest deterioration range. With the increase in erosion time, the deterioration rate gradually decreased; temperature had a significant threshold effect on the strength of carbonaceous shale, and a clear turning point appeared at about 200 °C. By simulating the deterioration effects of carbonaceous shale under the coupled action of chemical erosion and high temperature, it was found that the longer the duration of chemical erosion, the stronger the temperature sensitivity of carbonaceous shale, and the more serious the loss of compressive strength during the heating process. When the temperature was low, the strength of carbonaceous shale changed little, and some samples even showed an increase in strength; when the temperature was high, the strength of carbonaceous shale decreased significantly, showing deterioration characteristics. The numerical simulation method was compared and verified with the indoor test results, and it was found that the numerical calculation had a good agreement with the test results.

Investigation of Damage and Creep for Bedding's Carbonaceous Slate with Chemical Erosion Effect.

Tunnel projects in the southwestern mountainous area of China are in full swing. According to the tunnel burial depth, structural characteristics, and chemical erosion environments of the Lixiang railway tunnel, carbonaceous slate specimens obtained in the field were taken to experimentally investigate the physical, mechanical, and creep characteristics of the bedding's slate specimens after chemical erosion. The results of scanning electron microscopy (SEM) indicate that chemical erosion leads to internal damage in the carbonaceous slate specimens, and the internal damages are increasing with the increase of erosion days. Moreover, the specimens' ultrasonic test (UT) results prove that specimens with smaller bedding angles suffer a more serious erosion and induce more internal cracks. Under conventional triaxial compression conditions with 40 MPa of confining pressures, the conventional triaxial compressive strength (σs) decreases with the decrease of the bedding angle and the increase of erosion days, and the failure modes of the specimens are mainly controlled by oblique shear fractures and accompanied by the occurrence of slip dislocation fractures between the bedding inclination. Under creep conditions with 40 MPa of confining pressures, the final deformations of specimens are increasing with the increase of erosion days, which means the longer the erosion days, the greater the deformations. The failure modes of the specimens under creep conditions are controlled by shear fractures, and for the specimen with a 60° bedding angle and long-term erosion, there are block separations and many cavities along the shear planes. Therefore, more attention should be paid to prevent serious failure of the surrounding rock if the surrounding rock has a bedding angle of 60° or suffers long-term erosion.

Exploring the Muscle Metabolomics in the Mouse Model of Sepsis-Induced Acquired Weakness.

Background/Aim: We aimed to identify the differentially expressing metabolites (DEMs) in the muscles of the mouse model of sepsis-induced acquired weakness (sepsis-AW) using liquid chromatography-mass spectrometry (LC-MS). Materials and Methods: Sepsis by cecal ligation puncture (CLP) with lower limb immobilization was used to produce a sepsis-AW model. After this, the grip strength of the C57BL/6 male mice was investigated. The transmission electron microscopy was utilized to determine the pathological model. LC-MS was used to detect the metabolic profiles within the mouse muscles. Additionally, a statistically diversified analysis was carried out. Results: Compared to the sepsis group, 30 DEMs, including 17 upregulated and 13 down-regulated metabolites, were found in the sepsis-AW group. The enriched metabolic pathways including purine metabolism, valine/leucine/isoleucine biosynthesis, cGMP-PKG pathway, mTOR pathway, FoxO pathway, and PI3K-Akt pathway were found to differ between the two groups. The targeted metabolomics analysis explored significant differences between four amino acid metabolites (leucine, cysteine, tyrosine, and serine) and two energy metabolites (AMP and cAMP) in the muscles of the sepsis-AW experimental model group, which was comparable to the sepsis group. Conclusion: The present work identified DEMs and metabolism-related pathways within the muscles of the sepsis-AW mice, which offered valuable experimental data for diagnosis and identification of the pathogenic mechanism underlying sepsis-AW.

CHRNA1 induces sarcopenia through neuromuscular synaptic elimination.

Sarcopenia seriously affects the quality of life of the elderly, but its molecular mechanism is still unclear. Degeneration in muscle innervation is related to age-related movement disorders and muscle atrophy. The expression of CHRNA1 is increased in the skeletal muscle of the elderly, and in aging rodents. Therefore, we investigated whether CHRNA1 induces the occurrence and development of sarcopenia. Compared with the control group, local injection of AAV9-CHRNA1 into the hindlimb muscles decreased the percentage of muscle innervation. At the same time, the skeletal muscle mass decreased, as manifested by a decrease in the gastrocnemius mass index and the cross-sectional area of the muscle fibers. The function of skeletal muscle also decreased, which was manifested by decreases of compound muscle action potential and muscle contractility. Therefore, we concluded that upregulation of CHRNA1 can induce and aggravate sarcopenia.

MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging.

Age-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by D-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

Type 2 diabetes-induced overactivation of P300 contributes to skeletal muscle atrophy by inhibiting autophagic flux.

AIMS: Although autophagy impairment is a well-established cause of muscle atrophy and P300 has recently been identified as an important regulator of autophagy, the effects of P300 on autophagy and muscle atrophy in type 2 diabetes (T2D) remain unexplored. We aimed at characterizing the role of P300 in diabetic muscle and its underlying mechanism. MAIN METHODS: Protein levels of phosphorylated P300, total P300, acetylated histone H3, LC3, p62 and myosin heavy chain, and mRNA levels of Atrogin-1 and MuRF1 were analyzed in palmitic acid (PA)-treated myotubes and db/db mice. Autophagic flux was assessed using transmission electron microscopy, immunofluorescence and mRFP-GFP-LC3 lentivirus transfection in cells. Muscle weight, blood glucose and grip strength were measured in mice. Hematoxylin and eosin (H&E) staining was performed to determine changes in muscle fiber size. To investigate the effects of P300 on autophagy and myofiber remodeling, a P300 specific inhibitor, c646, was utilized. 3-Methyladenine (3-MA) was utilized to inhibit autophagosomes formation, and chloroquine (CQ) was used to block autophagic flux. KEY FINDINGS: Phosphorylation of P300 in response to PA enhanced its activity and subsequently suppressed autophagic flux, leading to atrophy-related morphological and molecular changes in myotubes. Inhibition of P300 reestablished autophagic flux and ameliorated PA-induced myotubes atrophy. However, this effect was largely abolished by co-treatment with the autophagy inhibitor CQ. In vivo results demonstrated that inhibition of P300 partially rescued muscle wasting in db/db mice, accompanied with autophagy reactivation. SIGNIFICANCE: The findings revealed that T2D-induced overactivation of P300 contributes to muscle atrophy by blocking autophagic flux.