bims-glecem 2022-12-25 papers

Issue of 2022–12–25
six papers selected by
Dipsikha Biswas, Københavns Universitet

Biomolecules. 2022 Nov 26. pii: 1755. [Epub ahead of print]12(12):

Protein Targeting to Glycogen (PTG): A Promising Player in Glucose and Lipid Metabolism.

Xia Deng, Chenxi Wang, Yue Xia, Guoyue Yuan.

Protein phosphorylation and dephosphorylation are widely considered to be the key regulatory factors of cell function, and are often referred to as "molecular switches" in the regulation of cell metabolic processes. A large number of studies have shown that the phosphorylation/dephosphorylation of related signal molecules plays a key role in the regulation of liver glucose and lipid metabolism. As a new therapeutic strategy for metabolic diseases, the potential of using inhibitor-based therapies to fight diabetes has gained scientific momentum. PTG, a protein phosphatase, also known as glycogen targeting protein, is a member of the protein phosphatase 1 (PP1) family. It can play a role by catalyzing the dephosphorylation of phosphorylated protein molecules, especially regulating many aspects of glucose and lipid metabolism. In this review, we briefly summarize the role of PTG in glucose and lipid metabolism, and update its role in metabolic regulation, with special attention to glucose homeostasis and lipid metabolism.

Keywords: glucose metabolism; glycogen synthesis; lipid metabolism; protein phosphatase 1α (PP1α); protein targeting to glycogen (PTG)

DOI: https://doi.org/10.3390/biom12121755

Continuum (Minneap Minn). 2022 Dec 01. 28(6): 1752-1777

Metabolic Myopathies.

Mark A Tarnopolsky.

PURPOSE OF REVIEW: Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies.
RECENT FINDINGS: Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies; however, they often overlap clinically with structural genetic myopathies, referred to as pseudometabolic myopathies. Although metabolic myopathies can present in the neonatal period with hypotonia, hypoglycemia, and encephalopathy, most cases present clinically in children or young adults with exercise intolerance, rhabdomyolysis, and weakness. In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever). The neurologic examination is often normal between events (except in the pseudometabolic myopathies) and evaluation requires one or more of the following tests: exercise stress testing, blood (eg, creatine kinase, acylcarnitine profile, lactate, amino acids), urine (eg, organic acids, myoglobin), muscle biopsy (eg, histology, ultrastructure, enzyme testing), and targeted (specific gene) or untargeted (myopathy panels) genetic tests.
SUMMARY: Definitive identification of a specific metabolic myopathy often leads to specific interventions, including lifestyle, exercise, and nutritional modifications; cofactor treatments; accurate genetic counseling; avoidance of specific triggers; and rapid treatment of rhabdomyolysis.

DOI: https://doi.org/10.1212/CON.0000000000001182

Nutrients. 2022 Dec 08. pii: 5222. [Epub ahead of print]14(24):

Polygonatum sibiricum saponin Exerts Beneficial Hypoglycemic Effects in Type 2 Diabetes Mice by Improving Hepatic Insulin Resistance and Glycogen Synthesis-Related Proteins.

Zefu Chen, Jiayuan Luo, Mingjie Jia, Yangyang Chai, Yihong Bao.

Type 2 diabetes mellitus (T2DM) is a systemic metabolic disorder characterized by insulin deficiency and insulin resistance. Recently, it has become a significant threat to public health. Polygonatum sibiricum saponin (PSS) has potential hypoglycemic effects, but its specific mechanism needs further study. In this study, PSS significantly decreased the level of blood glucose, water intake, and the organ index in diabetic mice. Meanwhile, PSS effectively reduced the content of total triglyceride (TG), total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the blood, and increased the content of high-density lipoprotein cholesterol (HDL-C). This suggests that PSS could reduce the content of blood lipids and initially improve the damage of hepatocytes. We found that PSS alleviated hepatic insulin resistance, repaired islet beta cells, and enabled insulin to play its biological role normally. It also improved oral glucose tolerance and abated serum lipopolysaccharide (LPS) and glycosylated hemoglobin (HbA1c) levels in T2DM mice. Furthermore, studies have found that PSS increased the content of phosphorylated protein kinase B (AKT), thereby promoting the effect of glucose transporter 4 (GLUT-4), and activating glycogen synthase kinase 3beta (GSK-3β) and glycogen synthase (GS) proteins to promote hepatic glycogen synthesis. Finally, we found that PSS could promote the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus, reduce the growth of harmful bacteria such as Enterococcus and Enterobacter, and preliminarily improve the composition of important bacteria in the intestine. These studies indicate that PSS has an excellent hypoglycemic effect, which provides a potential new treatment for T2DM and guidance for more in-depth research.

Keywords: Polygonatum sibiricum; Saponin; T2DM; glycogen synthesis; hepatic insulin resistance; hypoglycemic; important gut bacteria

DOI: https://doi.org/10.3390/nu14245222

Int J Mol Sci. 2022 Dec 09. pii: 15633. [Epub ahead of print]23(24):

Glycogen Synthase Kinase 3β Is a Key Regulator in the Inhibitory Effects of Accumbal Cocaine- and Amphetamine-Regulated Transcript Peptide 55-102 on Amphetamine-Induced Locomotor Activity.

Bo Ram Cho, Wha Young Kim, Ju Kyong Jang, Jung Won Lee, Jeong-Hoon Kim.

Microinjection of cocaine- and amphetamine-regulated transcript (CART) peptide 55-102 into the nucleus accumbens (NAcc) core significantly attenuates psychostimulant-induced locomotor activity. However, the molecular mechanism remains poorly understood. We examined the phosphorylation levels of Akt, glycogen synthase kinase 3β (GSK3β), and glutamate receptor 1 (GluA1) in NAcc core tissues obtained 60 min after microinjection of CART peptide 55-102 into this site, followed by systemic injection of amphetamine (AMPH). Phosphorylation levels of Akt at Thr308 and GSK3β at Ser9 were decreased, while those of GluA1 at Ser845 were increased, by AMPH treatment. These effects returned to basal levels following treatment with CART peptide 55-102. Furthermore, the negative regulatory effects of the CART peptide on AMPH-induced changes in phosphorylation levels and locomotor activity were all abolished by pretreatment with the S9 peptide, an artificially synthesized indirect GSK3β activator. These results suggest that the CART peptide 55-102 in the NAcc core plays a negative regulatory role in AMPH-induced locomotor activity by normalizing the changes in phosphorylation levels of Akt-GSK3β, and subsequently GluA1 modified by AMPH at this site. The present findings are the first to reveal GSK3β as a key regulator of the inhibitory role of the CART peptide in psychomotor stimulant-induced locomotor activity.

Keywords: CART; GSK3β; amphetamine; locomotor activity; nucleus accumbens

DOI: https://doi.org/10.3390/ijms232415633

Medicine (Baltimore). 2022 Dec 16. 101(50): e32209

High expression of GSKIP is associated with poor prognosis in meningioma.

Yu-Wen Cheng, Yang-Yi Chen, Chien-Ju Lin, Ann-Shung Lieu, Hung-Pei Tsai, Aij-Lie Kwan.

Meningiomas are the most common extra-axial primary central nervous system tumors. There is no effective treatment or targeted therapy for meningioma except excision and radiotherapy. glycogen synthesis kinase 3β interaction protein (GSKIP) is an A-kinase anchor protein that has cytosolic scaffolding function and binds to a protein kinase A and glycogen synthesis kinase 3β to modulate different biological processes and malignant tumorigenesis through the Wnt pathway. The purpose of this study was to investigate the relationship between GSKIP expression and the clinico-pathological parameters in meningioma using immunohistochemical staining. We collected samples from 74 patients, from 2008 to 2012, in the Kaohsiung Medical University Hospital that had data on the staging and prognosis of the meningioma pathological section. Chi-square, Kaplan-Meier method, and cox regression were used to analyze the correlation between clinical parameters and immunohistochemistry staining for GSKIP. Following our immunohistochemical score, we found that higher expression of GSKIP was associated with high World Health Organization grading, recurrence, malignant transformation, and reduced overall survival time and recurrence-free survival time in meningioma. GSKIP may be a biomarker of poor prognosis and a target protein for therapy in meningioma.

DOI: https://doi.org/10.1097/MD.0000000000032209

J Physiol. 2022 Dec 19.

A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle.

Ronald G Jones, Andrea Dimet-Wiley, Amin Haghani, Francielly Morena da Silva, Camille R Brightwell, Seongkyun Lim, Sabin Khadgi, Yuan Wen, Cory M Dungan, Robert T Brooke, Nicholas P Greene, Charlotte A Peterson, John J McCarthy, Steve Horvath, Stanley J Watowich, Christopher S Fry, Kevin A Murach.

KEY POINTS: Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodeling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2, and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing Using global gene expression analysis, we compared the effects of in vivo OKSM-mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late-life murine exercise training in muscle Myc is the Yamanaka factor most induced by exercise in skeletal muscle, so we compared the MYC-controlled transcriptome in muscle to Yamanaka factor-mediated and exercise adaptation gene landscapes in mice and humans A single pulse of MYC is sufficient to remodel the muscle methylome We identify partial reprogramming-associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses ABSTRACT: Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from 1) a skeletal muscle-specific in vivo Oct3/4, Klf4, Sox2, and Myc (OKSM) reprogramming-factor expression murine model, 2) an in vivo inducible muscle-specific Myc induction murine model, 3) a translatable high-volume hypertrophic exercise training approach in aged mice, and 4) human exercise muscle biopsies, we collectively defined exercise-induced genes that are common to partial reprogramming. Late-life exercise training lowered murine DNA methylation age according to several contemporary muscle-specific clocks. A comparison of the murine soleus transcriptome after late-life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle-enriched genes was conserved in skeletal muscle of long-term exercise-trained humans; among these was muscle-specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC-controlled and exercise adaptation transcriptomes, including lower muscle-specific Melusin and reactive oxygen species-associated Romo1. With Myc, OKSM, and exercise training in mice as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. Abstract figure legend Diverse forms of exercise training improve muscle function and whole-body health, even if initiated late in life. Information on conserved exercise-controlled molecular cues that underpin a younger muscle phenotype in aged muscle has potential utility in the development of anti-ageing therapies. Induction of the Yamanaka factors Oct3/4, Klf4, Sox2, and Myc are known to ameliorate ageing hallmarks. Comparison of transcriptomic data from aged exercise-trained mice and humans to muscle fibre-specific genetically driven models of epigenetic reprogramming (e.g. Yamanaka factor or Myc expression) unearthed conserved biomarkers associated with molecular age mitigation. Considering reduced biological age according to DNA methylome analysis, high-volume exercise training can be classified as an epigenetic reprogramming stimulus. Chronic exercise should be considered alongside and/or as a method to inform healthspan-extending longevity approaches such as pharmacologic and dietary interventions. This article is protected by copyright. All rights reserved.

Keywords: DNA methylation; MYC; Yamanaka factors; ageing

DOI: https://doi.org/10.1113/JP283836