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

Fan, Zhen; Wu, Jing; Chen, Qiunan; Lyu, Ankang; Chen, Jinliang; Sun, Yue; Lyu, Qiong; Zhao, Yutong; Guo, Ai; Liao, Zhiyin; Yang, Yunfei; Zhu, Shiyu; Jiang, Xu-shun; Chen, Bin; Xiao, Qian

doi:10.1016/j.lfs.2020.118243

Cited by 23 publications

(15 citation statements)

References 49 publications

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“…In vivo and in vitro, we found that FGF19 could inhibit the protein expression of muscle atrophy markers and enhanced the expression of myogenic differentiation‐related molecules. In addition, our previous research also investigated the effect of autophagy or apoptosis on obesity, T2D or sarcopenia‐induced muscle atrophy by mediating muscle degradation 37‐39 . However, the role of FGF19 in mediating autophagy‐lysosome systems might be a novel research target, further experiments are required.…”

Section: Discussionmentioning

confidence: 99%

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

Guo

Tian

et al. 2021

J Cellular Molecular Medi

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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.

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Section: Discussionmentioning

confidence: 99%

“…In addition, our previous research also investigated the effect of autophagy or apoptosis on obesity, T2D or sarcopeniainduced muscle atrophy by mediating muscle degradation. [37][38][39] However, the role of FGF19 in mediating autophagy-lysosome systems might be a novel research target, further experiments are required.…”

Section: Discussionmentioning

confidence: 99%

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

Guo

Tian

et al. 2021

J Cellular Molecular Medi

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“…According to the Pearson correlation analysis, bacteria-related metabolites participated in the alternation of meat quality and myofiber traits. The metabolite 3-methyladenine can act as an autophagy inhibitor in type 2 diabetes-induced skeletal muscle atrophy ( 77 ). Guanidoacetic acid was significantly related to meat quality traits and myofiber traits.…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Analysis of the Microbiome and Metabolome Reveals the Relationship Between the Gut Microbiota and Wooden Breast Myopathy in Broilers

et al. 2022

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Wooden breast (WB) is a widely prevalent myopathy in broiler chickens. However, the role of the gut microbiota in this myopathy remains largely unknown, in particular the regulatory effect of gut microbiota in the modulation of muscle metabolism. Totally, 300 1-day-old Arbor Acres broilers were raised until 49 days and euthanized, and the breast filets were classified as normal (NORM), mild (MILD), or severe wooden breast (SEV). Birds with WB comprised 27.02% of the individuals. Severe WB filets had a greater L* value, a* value, and dripping loss but a lower pH (P < 0.05). WB filets had abundant myofiber fragmentation, with a lower average myofiber caliber and more fibers with a diameter of <20 μm (P < 0.05). The diversity of the intestinal microflora was decreased in birds with severe WB, with decreases in Chao 1, and observed species indices. At the phylum level, birds with severe WB had a lower Firmicutes/Bacteroidetes ratio (P = 0.098) and a decreased abundance of Verrucomicrobia (P < 0.05). At the species level, gut microbiota were positively correlated with 131 digesta metabolites in pathways of glutamine and glutamate metabolism and arginine biosynthesis but were negatively correlated with 30 metabolites in the pathway of tyrosine metabolism. In plasma, WB induced five differentially expressed metabolites (DEMs), including anserine and choline, which were related to the severity of the WB lesion. The microbial-derived metabolites, including guanidoacetic acid, antiarol, and (2E)-decenoyl-ACP, which entered into plasma were related to meat quality traits and myofiber traits. In summary, WB filets differed in gut microbiota, digesta, and plasma metabolites. Gut microbiota respond to the wooden breast myopathy by driving dynamic changes in digesta metabolites that eventually enter the plasma.

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“…Apart from beneficial effects demonstrated in different experimental models of cancer [ 49 ], it has been increasingly shown that pharmacological targeting of the up-regulated p300/CBP activity with C646 inhibitor represents a promising way to intervene in the progression of metabolic and cardiovascular disorders. Reportedly, C646 reduced skeletal muscle atrophy in db/db mice, an experimental model of type 2 diabetes [ 50 ]. In addition, C646-mediated blockade of p300 improved coronary flow in an experimental model of heart failure [ 33 ] and reduced cardiac fibrosis in hypertensive mice [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Activated Histone Acetyltransferase p300/CBP-Related Signalling Pathways Mediate Up-Regulation of NADPH Oxidase, Inflammation, and Fibrosis in Diabetic Kidney

et al. 2021

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Accumulating evidence implicates the histone acetylation-based epigenetic mechanisms in the pathoetiology of diabetes-associated micro-/macrovascular complications. Diabetic kidney disease (DKD) is a progressive chronic inflammatory microvascular disorder ultimately leading to glomerulosclerosis and kidney failure. We hypothesized that histone acetyltransferase p300/CBP may be involved in mediating diabetes-accelerated renal damage. In this study, we aimed at investigating the potential role of p300/CBP in the up-regulation of renal NADPH oxidase (Nox), reactive oxygen species (ROS) production, inflammation, and fibrosis in diabetic mice. Diabetic C57BL/6J mice were randomized to receive 10 mg/kg C646, a selective p300/CBP inhibitor, or its vehicle for 4 weeks. We found that in the kidney of C646-treated diabetic mice, the level of H3K27ac, an epigenetic mark of active gene expression, was significantly reduced. Pharmacological inhibition of p300/CBP significantly down-regulated the diabetes-induced enhanced expression of Nox subtypes, pro-inflammatory, and pro-fibrotic molecules in the kidney of mice, and the glomerular ROS overproduction. Our study provides evidence that the activation of p300/CBP enhances ROS production, potentially generated by up-regulated Nox, inflammation, and the production of extracellular matrix proteins in the diabetic kidney. The data suggest that p300/CBP-pharmacological inhibitors may be attractive tools to modulate diabetes-associated pathological processes to efficiently reduce the burden of DKD.

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

Cited by 23 publications

References 49 publications

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

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

Multi-Omics Analysis of the Microbiome and Metabolome Reveals the Relationship Between the Gut Microbiota and Wooden Breast Myopathy in Broilers

Activated Histone Acetyltransferase p300/CBP-Related Signalling Pathways Mediate Up-Regulation of NADPH Oxidase, Inflammation, and Fibrosis in Diabetic Kidney

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