bims-glecem 2022-10-30 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–10–30
six papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism.
Glycogen Synthase Kinase 3β (GSK3β) Regulates Myogenic Differentiation in Skeletal Muscle Satellite Cells of Sheep.
IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy.
Mulberry (Morus alba L.) Leaf Extract and 1-Deoxynojirimycin Improve Skeletal Muscle Insulin Resistance via the Activation of IRS-1/PI3K/Akt Pathway in db/db Mice.
Monascus-fermented grain vinegar enhances glucose homeostasis through the IRS-1/PI3K/Akt and AMPK signaling pathways in HepG2 cell and db/db mice.
Comparison between low, moderate, and high intensity aerobic training with equalized loads on biomarkers and performance in rats.

Heliyon. 2022 Oct;8(10): e11091

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism.

Ryan M Esquejo, Bina Albuquerque, Anna Sher, Matthew Blatnik, Kyle Wald, Matthew Peloquin, Jake Delmore, Erick Kindt, Wenlin Li, Jamey D Young, Kim Cameron, Russell A Miller.

  The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.

Keywords:  AMPK; Metabolism; Pharmacology; Skeletal muscle

DOI:  https://doi.org/10.1016/j.heliyon.2022.e11091
Animals (Basel). 2022 Oct 15. pii: 2789. [Epub ahead of print]12(20):

Glycogen Synthase Kinase 3β (GSK3β) Regulates Myogenic Differentiation in Skeletal Muscle Satellite Cells of Sheep.

Jingquan Yang, Haosen Yang, Linjie Wang, Ping Zhou.

  Glycogen synthase kinase 3β (GSK3β) has a vital role in the regulation of many cellular processes. However, the role of GSK3β in muscle cell differentiation in sheep remains unknown. In this study, we investigated the function of GSK3β in skeletal muscle satellite cells (SMSCs) of sheep. An overexpression of GSK3β significantly inhibited myotube formation as well as the mRNA levels of myogenic genes (MyoD, MyoG, MyHC1, and MyHC2a) in sheep SMSCs. SB216763 treatment had a time-course effect on the phosphorylation levels of sheep GSK3β. In addition, reducing the activity of GSK3β lead to the promotion of sheep SMSCs differentiation as well as the mRNA levels of myogenic genes (MyoD, MyoG, MyHC1, and MyHC2a). This study illustrated the function of GSK3β to inhibit myogenesis in sheep SMSCs, which provided evidence for studying the mechanisms involved in the regulation of sheep SMSCs differentiation by GSK3β.

Keywords:  GSK3β; SB216763; satellite cells; sheep; skeletal muscle

DOI:  https://doi.org/10.3390/ani12202789
Mol Ther Methods Clin Dev. 2022 Dec 08. 27 109-130

IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy.

Qiushi Liang, Fabio Catalano, Eva C Vlaar, Joon M Pijnenburg, Merel Stok, Yvette van Helsdingen, Arnold G Vulto, Ans T van der Ploeg, Niek P van Til, W W M Pim Pijnappel.

  Pompe disease is caused by deficiency of acid α-glucosidase (GAA), resulting in glycogen accumulation in various tissues, including cardiac and skeletal muscles and the central nervous system (CNS). Enzyme replacement therapy (ERT) improves cardiac, motor, and respiratory functions but is limited by poor cellular uptake and its inability to cross the blood-brain barrier. Previously, we showed that hematopoietic stem cell (HSPC)-mediated lentiviral gene therapy (LVGT) with codon-optimized GAA (LV-GAAco) caused glycogen reduction in heart, skeletal muscles, and partially in the brain at high vector copy number (VCN). Here, we fused insulin-like growth factor 2 (IGF2) to a codon-optimized version of GAA (LV-IGF2.GAAco) to improve cellular uptake by the cation-independent mannose 6-phosphate/IGF2 (CI-M6P/IGF2) receptor. In contrast to LV-GAAco, LV-IGF2.GAAco was able to completely normalize glycogen levels, pathology, and impaired autophagy at a clinically relevant VCN of 3 in heart and skeletal muscles. LV-IGF2.GAAco was particularly effective in treating the CNS, as normalization of glycogen levels and neuroinflammation was achieved at a VCN between 0.5 and 3, doses at which LV-GAAco was largely ineffective. These results identify IGF2.GAA as a candidate transgene for future clinical development of HSPC-LVGT for Pompe disease.

Keywords:  GAA; IGF2; Pompe; gene therapy; glycogen storage disease; hematopoietic; lentiviral

DOI:  https://doi.org/10.1016/j.omtm.2022.09.010
Life (Basel). 2022 Oct 18. pii: 1630. [Epub ahead of print]12(10):

Mulberry (Morus alba L.) Leaf Extract and 1-Deoxynojirimycin Improve Skeletal Muscle Insulin Resistance via the Activation of IRS-1/PI3K/Akt Pathway in db/db Mice.

Chae-Won Kang, Miey Park, Hae-Jeung Lee.

  Mulberry (Morus alba L.) leaves have been used to lower blood glucose in patients with diabetes. We evaluated the effects of mulberry leaves extract (MLE) and 1-deoxynojirimycin (1-DNJ) in improving insulin resistance through the activation of the IRS-1/PI3K/Akt pathway in the skeletal muscle of db/db mice. Histological analysis revealed an amelioration of muscle deformation and increased muscle fiber size. MLE and 1-DNJ positively raised the protein expression of related glucose uptake and increased the translocation of glucose transporter type 4 (GLUT4) to the membrane. Furthermore, MLE and 1-DNJ activated the IRS-1/PI3K/Akt pathway in the skeletal muscle and, subsequently, modulated the protein levels of glycogen synthase kinase-3beta (GSK-3β) and glycogen synthase (GS), leading to elevated muscle glycogen content. These findings suggest that MLE and 1-DNJ supplementation improves insulin resistance by modulating the insulin signaling pathway in the skeletal muscle of db/db mice.

Keywords:  1-deoxynojirimycin; IRS-1/PI3K/Akt pathway; Morus alba L.; db/db mice; skeletal muscle; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/life12101630
Food Sci Biotechnol. 2022 Nov;31(12): 1583-1591

Monascus-fermented grain vinegar enhances glucose homeostasis through the IRS-1/PI3K/Akt and AMPK signaling pathways in HepG2 cell and db/db mice.

Ye-Won Lee, Young-Hee Pyo.

  MV was reported to have beneficial effects in ameliorating insulin resistance in db/db mice, but the intrinsic mechanisms for glucose homeostasis are unclear. This study examined the anti-diabetic mechanism of MV using HepG2 cells and C57BL/KsJ-db/db mice. MV increased insulin sensitivity by promoting insulin-dependent glucose uptake and activating glycogen accumulation in HepG2 cells. Furthermore, the glucose homeostasis was enhanced in db/db mice administered 1 mg/kg/day of MV for eight weeks by activating the IRS-1/PI3K/Akt and AMPK pathways in the skeletal muscle and liver tissue. In addition, MV promoted glycogen synthesis by regulating the key enzymes, including GSK-3β and GS, and suppressed gluconeogenesis by inhibiting the mRNA expressions of G6pase and PEPCK. These findings show that MV regulates both signaling pathways and improves the glucose metabolism disorder. Thus, MV might be an alternative functional food or nutraceutical in ameliorating T2DM.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01146-4.

Keywords:  Db/db mouse; Glucose homeostasis; Monascus-vinegar; T2DM

DOI:  https://doi.org/10.1007/s10068-022-01146-4
Sci Rep. 2022 Oct 27. 12(1): 18047

Comparison between low, moderate, and high intensity aerobic training with equalized loads on biomarkers and performance in rats.

Carlos Dellavechia de Carvalho, Rafael Rossi Valentim, Luiz Carlos Carvalho Navegantes, Marcelo Papoti.

This study investigated the physiological and molecular responses of Wistar Hannover rats, submitted to three 5-week chronic training models, with similar training loads. Twenty-four Wistar Hanover rats were randomly divided into four groups: control (n = 6), low-intensity training (Z1; n = 6), moderate-intensity training (Z2; n = 6) and high-intensity training (Z3; n = 6). The three exercise groups performed a 5-week running training three times a week, with the same prescribed workload but the intensity and the volume were different between groups. An increase in maximal speed was observed after four weeks of training for the three groups that trained, with no difference between groups. Higher rest glycogen was also observed in the soleus muscle after training for the exercise groups compared to the control group. We also found that the Z2 group had a higher protein content of total and phosphorylated GSK3-β compared to the control group after five weeks of training. In conclusion, the present study shows that five weeks of treadmill training based on intensity zones 1, 2, and 3 improved performance and increased resting glycogen in the soleus muscle, therefore intensity modulation does not change the training program adaptation since the different program loads are equalized.

DOI: https://doi.org/10.1038/s41598-022-22958-8