bims-glecem 2024-02-04 papers

Issue of 2024–02–04
five papers selected by
Dipsikha Biswas, Københavns Universitet

J Clin Invest. 2024 Jan 30. pii: e173782. [Epub ahead of print]

mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.

Kahealani Uehara, Won Dong Lee, Megan Stefkovich, Dipsikha Biswas, Dominic Santoleri, Anna E Garcia Whitlock, William J Quinn Iii, Talia N Coopersmith, Kate Townsend Creasy, Daniel J Rader, Kei Sakamoto, Joshua D Rabinowitz, Paul M Titchenell.

In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Re-expression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis.

Keywords: Endocrinology; Glucose metabolism; Insulin signaling; Metabolism

DOI: https://doi.org/10.1172/JCI173782

PLoS One. 2024 ;19(1): e0295964

A novel genetic model provides a unique perspective on the relationship between postexercise glycogen concentration and increases in the abundance of key metabolic proteins after acute exercise.

Seong Eun Kwak, Amy Zheng, Edward B Arias, Haiyan Wang, Xiufang Pan, Yongping Yue, Dongsheng Duan, Gregory D Cartee.

Some acute exercise effects are influenced by postexercise (PEX) diet, and these diet-effects are attributed to differential glycogen resynthesis. However, this idea is challenging to test rigorously. Therefore, we devised a novel genetic model to modify muscle glycogen synthase 1 (GS1) expression in rat skeletal muscle with an adeno-associated virus (AAV) short hairpin RNA knockdown vector targeting GS1 (shRNA-GS1). Contralateral muscles were injected with scrambled shRNA (shRNA-Scr). Muscles from exercised (2-hour-swim) and time-matched sedentary (Sed) rats were collected immediately postexercise (IPEX), 5-hours-PEX (5hPEX), or 9-hours-PEX (9hPEX). Rats in 5hPEX and 9hPEX experiments were refed (RF) or not-refed (NRF) chow. Muscles were analyzed for glycogen, abundance of metabolic proteins (pyruvate dehydrogenase kinase 4, PDK4; peroxisome proliferator-activated receptor γ coactivator-1α, PGC1α; hexokinase II, HKII; glucose transporter 4, GLUT4), AMP-activated protein kinase phosphorylation (pAMPK), and glycogen metabolism-related enzymes (glycogen phosphorylase, PYGM; glycogen debranching enzyme, AGL; glycogen branching enzyme, GBE1). shRNA-GS1 versus paired shRNA-Scr muscles had markedly lower GS1 abundance. IPEX versus Sed rats had lower glycogen and greater pAMPK, and neither of these IPEX-values differed for shRNA-GS1 versus paired shRNA-Scr muscles. IPEX versus Sed groups did not differ for abundance of metabolic proteins, regardless of GS1 knockdown. Glycogen in RF-rats was lower for shRNA-GS1 versus paired shRNA-Scr muscles at both 5hPEX and 9hPEX. HKII protein abundance was greater for 5hPEX versus Sed groups, regardless of GS1 knockdown or diet, and despite differing glycogen levels. At 9hPEX, shRNA-GS1 versus paired shRNA-Scr muscles had greater PDK4 and PGC1α abundance within each diet group. However, the magnitude of PDK4 or PGC1α changes was similar in each diet group regardless of GS1 knockdown although glycogen differed between paired muscles only in RF-rats. In summary, we established a novel genetic approach to investigate the relationship between muscle glycogen and other exercise effects. Our results suggest that exercise-effects on abundance of several metabolic proteins did not uniformly correspond to differences in postexercise glycogen.

DOI: https://doi.org/10.1371/journal.pone.0295964

J Proteomics. 2024 Jan 16. pii: S1874-3919(23)00226-9. [Epub ahead of print]291 105037

Lentiviral gene therapy with IGF2-tagged GAA normalizes the skeletal muscle proteome in murine Pompe disease.

Qiushi Liang, Eva C Vlaar, Joon M Pijnenburg, Erikjan Rijkers, Jeroen A A Demmers, Arnold G Vulto, Ans T van der Ploeg, Niek P van Til, W W M Pim Pijnappel.

Pompe disease is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), resulting in glycogen accumulation with profound pathology in skeletal muscle. We recently developed an optimized form of lentiviral gene therapy for Pompe disease in which a codon-optimized version of the GAA transgene (LV-GAAco) was fused to an insulin-like growth factor 2 (IGF2) peptide (LV-IGF2.GAAco), to promote cellular uptake via the cation-independent mannose-6-phosphate/IGF2 receptor. Lentiviral gene therapy with LV-IGF2.GAAco showed superior efficacy in heart, skeletal muscle, and brain of Gaa -/- mice compared to gene therapy with untagged LV-GAAco. Here, we used quantitative mass spectrometry using TMT labeling to analyze the muscle proteome and the response to gene therapy in Gaa -/- mice. We found that muscle of Gaa -/- mice displayed altered levels of proteins including those with functions in the CLEAR signaling pathway, autophagy, cytoplasmic glycogen metabolism, calcium homeostasis, redox signaling, mitochondrial function, fatty acid transport, muscle contraction, cytoskeletal organization, phagosome maturation, and inflammation. Gene therapy with LV-GAAco resulted in partial correction of the muscle proteome, while gene therapy with LV-IGF2.GAAco resulted in a near-complete restoration to wild type levels without inducing extra proteomic changes, supporting clinical development of lentiviral gene therapy for Pompe disease. SIGNIFICANCE: Lysosomal glycogen accumulation is the primary cause of Pompe disease, and leads to a cascade of pathological events in cardiac and skeletal muscle and in the central nervous system. In this study, we identified the proteomic changes that are caused by Pompe disease in skeletal muscle of a mouse model. We showed that lentiviral gene therapy with LV-IGF2.GAAco nearly completely corrects disease-associated proteomic changes. This study supports the future clinical development of lentiviral gene therapy with LV-IGF2.GAAco as a new treatment option for Pompe disease.

Keywords: Acid-alpha glucosidase; Glycogen storage disease type II; Lentiviral gene therapy; Lysosomal storage disease; Pompe disease; Proteome

DOI: https://doi.org/10.1016/j.jprot.2023.105037

J Biosci. 2024 ;pii: 22. [Epub ahead of print]49

Lafora progressive myoclonus epilepsy: Disease mechanism and therapeutic attempts.

Rashmi Parihar, Subramaniam Ganesh.

Lafora disease (LD) is a life-threatening autosomal recessive and progressive neurodegenerative disorder that primarily affects adolescents, resulting in mortality within a decade of onset. The symptoms of LD include epileptic seizures, ataxia, dementia, and psychosis. The underlying pathology involves the presence of abnormal glycogen inclusions in neurons and other tissues, which may contribute to neurodegeneration. LD is caused by loss-of-function mutations in either the EPM2A gene or the NHLRC1 gene. These two genes, respectively, code for laforin phosphatase and malin ubiquitin ligase, and are thought to function, as a functional complex, in diverse cellular pathways. One of the major pathways affected in LD is glycogen metabolism; defects here lead to abnormally higher levels of glycogen and its hyperphosphorylation and aggregation, resulting in the formation of Lafora inclusion bodies. Currently, there is no effective therapy for LD. Studies, particularly from animal models, provide distinct insights into the fundamental mechanisms of diseases and potential avenues for therapeutic interventions. The purpose of this review is to present a comprehensive overview of our current knowledge regarding the disease, its genetics, the animal models that have been developed, and the therapeutic strategies that are being developed based on an understanding of the disease mechanism.

Gene. 2024 Jan 31. pii: S0378-1119(24)00097-0. [Epub ahead of print] 148216

Molecular Effects of Vitamin-D and PUFAs metabolism in Skeletal Muscle combating Type-II Diabetes mellitus.

Rajan Logesh, Balaji Hari, Kumarappan Chidambaram, Niranjan Das.

Multiple post-receptor intracellular alterations such as impaired glucose transfer, glucose phosphorylation, decreased glucose oxidation, and glycogen production contribute to insulin resistance (IR) in skeletal muscle, manifested by diminished insulin-stimulated glucose uptake. Type-2 diabetes mellites (T2DM) has caused by IR, which is also seen in obese patients and those with metabolic syndrome. The Vitamin-D receptor (VDR) and poly unsaturated fatty acids (PUFAs) roles in skeletal muscle growth, shapes, and function for combating type-2 diabetes have been clarified throughout this research. VDR and PUFAs appears to show a variety of effects on skeletal muscle, in addition it shows a promising role on bone and mineral homeostasis. Individuals having T2DM are reported to suffer from severe muscular weakness and alterations in shape of the muscle. Several studies have investigated the effect on VDR on muscular strength and mass, which leads to Vitamin-D deficiency (VDD) in individuals, in which most commonly seen in elderly. VDR has been shown to affect skeletal cellular proliferation, intracellular calcium handling, as well as genomic activity in a variety of different ways such as muscle metabolism, insulin sensitivity, which is the major characteristic pathogenesis for IR in combating T2DM. The identified VDR gene polymorphisms are ApaI, TaqI, FokI, and BsmI that are associated with T2DM. This review collates informations on the mechanisms by which VDR activation takes place in skeletal muscles. Despite the significant breakthroughs made in recent decades, various studies show that IR affects VDR and PUFAs metabolism in skeletal muscle. Therefore, this review collates the data to show the role of VDR and PUFAs in the skeletal muscles to combat T2DM.

Keywords: Insulin Resistance; Polyunsaturated Fatty acids; Skeletal muscles; Type 2 Diabetes Mellitus; Vitamin D receptor

DOI: https://doi.org/10.1016/j.gene.2024.148216