bims-glecem 2022-07-24 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–07–24
nine papers selected by
Dipsikha Biswas, Københavns Universitet

The Role of Muscle Glycogen Content and Localization in High-Intensity Exercise Performance: A Placebo-Controlled Trial.
Muscle MRI in McArdle Disease: A European Multicenter Observational Study.
Endometrial glycogen metabolism during early pregnancy in mice.
Manipulating the Expression of Glycogen Phosphorylase in Synechococcus elongatus PCC 7942 to Mobilize Glycogen Storage for Sucrose Synthesis.
Hepatic glycogen storage diseases type 0, VI and IX: description of an italian cohort.
Influence of menstrual cycle on muscle glycogen utilization during high-intensity intermittent exercise until exhaustion in healthy women.
Aggressive immunotherapy combined with bortezomib and rituximab for membranous nephropathy associated with enzyme replacement therapy in Pompe disease.
Body composition in patients with hepatic glycogen storage diseases.
Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis.

Med Sci Sports Exerc. 2022 Jul 16.

The Role of Muscle Glycogen Content and Localization in High-Intensity Exercise Performance: A Placebo-Controlled Trial.

Jeppe F Vigh-Larsen, Niels Ørtenblad, Joachim Nielsen, Ole E Andersen, Kristian Overgaard, Magni Mohr.

PURPOSE: We investigated the coupling between muscle glycogen content and localization and high-intensity exercise performance using a randomized, placebo-controlled, parallel-group design with emphasis on single-fiber subcellular glycogen concentrations and sarcoplasmic reticulum Ca2+ kinetics.
METHODS: Eighteen well-trained participants performed high-intensity intermittent glycogen-depleting exercise followed by randomization to a high- (CHO, ~1 g CHO·kg-1·h-1, n = 9) or low-carbohydrate placebo diet (PLA, <0.1 g CHO·kg-1·h-1, n = 9) for a 5-h recovery period. At baseline, post-exercise and following the carbohydrate manipulation assessments of repeated sprint ability (5 x 6-s maximal cycling sprints w. 24 s of rest), neuromuscular function and ratings of perceived exertion during standardized high-intensity cycling (~90% Wmax) were performed, while muscle and blood samples were collected.
RESULTS: The exercise and carbohydrate manipulations led to distinct muscle glycogen concentrations in CHO and PLA at the whole-muscle (291 ± 78 vs 175 ± 100 mmol·kg-1 dw, P = 0.020) and subcellular level in each of three local regions (P = 0.001-0.046). This was coupled with near-depleted glycogen concentrations in single-fibers of both main fiber types in PLA, especially in the intramyofibrillar region (within the myofibrils). Furthermore, increased ratings of perceived exertion and impaired repeated sprint ability (~8% loss, P < 0.001) were present in PLA, the latter correlating moderately to very strongly (r = 0.47-0.71, P = 0.001-0.049) with whole-muscle glycogen and subcellular glycogen fractions. Finally, sarcoplasmic reticulum Ca2+ uptake, but not release, was superior in CHO, whereas neuromuscular function, including prolonged low-frequency force depression, was unaffected by dietary manipulation.
CONCLUSIONS: Together, these results support an important role of muscle glycogen availability for high-intensity exercise performance, which may be mediated by reductions in single-fiber levels, particularly in distinct subcellular regions, despite only moderately lowered whole-muscle glycogen concentrations.

DOI: https://doi.org/10.1249/MSS.0000000000003002
Neurology. 2022 Jul 19. pii: 10.1212/WNL.0000000000200914. [Epub ahead of print]

Muscle MRI in McArdle Disease: A European Multicenter Observational Study.

Nicoline Løkken, Karoline Lolk Revsbech, Laura Nørager Jacobsen, Andrea Martinuzzi, Miguel Ángel Martin, Jordi Díaz-Manera, Cristina Dominguez-Gonzalez, Giovanni Brondani, Olimpia Musumeci, Francesca Granata, Cristina Stefan, Concepción Merino-Sanchez, Claudia Nuñez Peralta, Tahmina Khawajazada, Jorge Alonso-Pérez, Antonio Toscano, John Vissing.

BACKGROUND AND OBJECTIVES: Glycogen storage disease type V (GSDV) or McArdle disease is a muscle glycogenosis that classically manifests with exercise intolerance and exercise-induced muscle pain. Muscle weakness and wasting may occur but is typically mild and described as located around the shoulder-girdle in elderly patients. Paraspinal muscle involvement has received little attention in the literature. The present study aimed to quantify fat-replacement of paraspinal, shoulder and lower limb muscles by magnetic resonance imaging in a European cohort of GSDV patients.
METHODS: This observational study included patients with verified GSDV and healthy controls (HC). Whole-body MR-images and clinical data were collected. The degree of muscle fat-replacement was evaluated on T1-weighted images with the semi-quantitative visual Mercuri-scale, and on Dixon-images where individual muscle fat fractions (FF) were quantitatively calculated.
RESULTS: MR-images and clinical data from a total of 57 GSDV patients (age 44.3±15.2 years) from five European centers were assessed and compared to findings in 30 HC (age 42.4±14.8 years). Patients with GSDV had significantly more fat-replacement of theparaspinal muscles compared to HC on all levels investigated detected both by the Mercuri and the Dixon methods (Dixon, paraspinal composite-FF (GSDV vs HC), at the cervical-: 31.3±13.1 vs 15.4±7.8; thoracic-: 34.5±19.0 vs 16.9±8.6 and lumbar-level: 43.9±19.6 vs 21.8±10.2 (p<0.0001)). Patients with GSDV also had significantly more fat-replacement of the shoulder muscles (evaluated by the Mercuri-scale), along with significantly, but numerically less, fat-replacement of thigh- and calf muscles compared to HC (Dixon, lower limb composite-FF (GSDV vs HC) at the thigh-: 12.0±5.6 vs 8.8±2.7 and calf-level: 13.1±6.7 vs 9.1±2.9 (p≤0.05)).
DISCUSSION: The primary findings are that patients with GSDV exhibit severe fat-replacement of the paraspinal muscles, which can have important implications for the future management of patients with GSDV, and also significant fat-replacement of shoulder-girdle muscles as previously described. The clinical relevance of the discrete increases in lower limb FF is uncertain. The changes were found to be age-related in both groups, but an accelerated effect was found in GSDV, probably due to continuous muscle damage.

DOI: https://doi.org/10.1212/WNL.0000000000200914
Mol Reprod Dev. 2022 Jul 17.

Endometrial glycogen metabolism during early pregnancy in mice.

Ziting Chen, Kassandra Sandoval, Matthew Dean.

  Glucose is critical during early pregnancy. The uterus can store glucose as glycogen but uterine glycogen metabolism is poorly understood. This study analyzed glycogen storage and localization of glycogen metabolizing enzymes from proestrus until implantation in the murine uterus. Quantification of diastase-labile periodic acid-Schiff (PAS) staining showed glycogen in the glandular epithelium decreased 71.4% at 1.5 days postcoitum (DPC) and 62.13% at DPC 3.5 compared to proestrus. In the luminal epithelium, glycogen was the highest at proestrus, decreased 46.2% at DPC 1.5 and 63.2% at DPC 3.5. Immunostaining showed that before implantation, glycogen metabolizing enzymes were primarily localized to the glandular and luminal epithelium. Stromal glycogen was low from proestrus to DPC 3.5. However, at the DPC 5.5 implantation sites, stromal glycogen levels increased sevenfold. Similarly, artificial decidualization resulted in a fivefold increase in glycogen levels. In both models, decidualization increased expression of glycogen synthase as determine by immunohistochemistry and western blot. In conclusion, glycogen levels decreased in the uterine epithelium before implantation, indicating that it could be used to support preimplantation embryos. Decidualization resulted in a dramatic increase in stromal glycogen levels, suggesting it may have an important, but yet undefined, role in pregnancy.

Keywords:  decidualization; glucose; glucose-6-phosphatase; glycogen phosphorylase; glycogen synthase; hexokinase

DOI:  https://doi.org/10.1002/mrd.23634
Front Bioeng Biotechnol. 2022 ;10 925311

Manipulating the Expression of Glycogen Phosphorylase in Synechococcus elongatus PCC 7942 to Mobilize Glycogen Storage for Sucrose Synthesis.

Yu Dan, Jiahui Sun, Shanshan Zhang, Yannan Wu, Shaoming Mao, Guodong Luan, Xuefeng Lu.

  Cyanobacteria are a promising photosynthetic chassis to produce biofuels, biochemicals, and pharmaceuticals at the expense of CO2 and light energy. Glycogen accumulation represents a universal carbon sink mechanism among cyanobacteria, storing excess carbon and energy from photosynthesis and may compete with product synthesis. Therefore, the glycogen synthesis pathway is often targeted to increase cyanobacterial production of desired carbon-based products. However, these manipulations caused severe physiological and metabolic impairments and often failed to optimize the overall performance of photosynthetic production. Here, in this work, we explored to mobilize the glycogen storage by strengthening glycogen degradation activities. In Synechococcus elongatus PCC 7942, we manipulated the abundances of glycogen phosphorylase (GlgP) with a theophylline dose-responsive riboswitch approach, which holds control over the cyanobacterial glycogen degradation process and successfully regulated the glycogen contents in the recombinant strain. Taking sucrose synthesis as a model, we explored the effects of enhanced glycogen degradation on sucrose production and glycogen storage. It is confirmed that under non-hypersaline conditions, the overexpressed glgP facilitated the effective mobilization of glycogen storage and resulted in increased secretory sucrose production. The findings in this work provided fresh insights into the area of cyanobacteria glycogen metabolism engineering and would inspire the development of novel metabolic engineering approaches for efficient photosynthetic biosynthesis.

Keywords:  Synechococcus elongatus PCC7942; cyanobacteria; glycogen; glycogen phosphorylase; sucrose

DOI:  https://doi.org/10.3389/fbioe.2022.925311
Orphanet J Rare Dis. 2022 Jul 19. 17(1): 285

Hepatic glycogen storage diseases type 0, VI and IX: description of an italian cohort.

Francesco Tagliaferri, Miriam Massese, Luisa Russo, Anna Commone, Serena Gasperini, Roberta Pretese, Carlo Dionisi-Vici, Arianna Maiorana.

   BACKGROUND: Glycogen storage disease (GSD) type 0, VI and IX are inborn errors of metabolism involving hepatic glycogen synthesis and degradation. We performed a characterization of a large Italian cohort of 30 patients with GSD type 0a, VI, IXa, IXb and IXc. A retrospective evaluation of genetical, auxological and endocrinological data, biochemical tests, and nutritional intakes was assessed. Eventual findings of overweight/obesity and insulin-resistance were correlated with diet composition.
RESULTS: Six GSD-0a, 1 GSD-VI, and 23 GSD-IX patients were enrolled, with an age of presentation from 0 to 72 months (median 14 months). Diagnosis was made at a median age of 30 months, with a median diagnostic delay of 11 months and a median follow-up of 66 months. From first to last visit, patients gained a median height of 0.6 SDS (from - 1.1 to 2.1 SDS) and a median weight of 0.5 SDS (from - 2.5 to 3.3 SDS); mean and minimal glucose values significant improved (p < 0.05). With respect to dietary intakes, protein intake (g/kg) and protein intake (g/kg)/RDA ratio directly correlated with the glucose/insulin ratio (p < 0.05) and inversely correlated with HOMA-IR (Homeostasis model assessment of insulin resistance, p < 0.05), BMI SDS (p < 0.05) and %ibw (ideal body weight percentage, p < 0.01).
CONCLUSION: A prompt establishment of specific nutritional therapy allowed to preserve growth, improve glycemic control and prevent liver complication, during childhood. Remarkably, the administration of a high protein diet appeared to have a protective effect against overweight/obesity and insulin-resistance.

Keywords:  Glycogen storage disease; Insulin-resistance; Liver; Nutrition; Nutritional therapy; Obesity; Overweight

DOI:  https://doi.org/10.1186/s13023-022-02431-5
Appl Physiol Nutr Metab. 2022 Jul 20.

Influence of menstrual cycle on muscle glycogen utilization during high-intensity intermittent exercise until exhaustion in healthy women.

Tomoka Matsuda, Hideyuki Takahashi, Mariko Nakamura, Moe Kanno, Hazuki Ogata, Akira Ishikawa, Mizuki Yamada, Kayoko Kamemoto, Mikako Sakamaki-Sunaga.

  The present study investigated the effects of the menstrual cycle on muscle glycogen and circulating substrates during high-intensity intermittent exercise until exhaustion in healthy women who habitually exercised. In total, 11 women with regular menstrual cycles completed three tests, which comprised the early follicular phase (E-FP), late follicular phase (L-FP), and luteal phase (LP) of the menstrual cycle. High-intensity intermittent exercise until exhaustion was performed on each test day. Evaluation of muscle glycogen concentration by 13C-magnetic resonance spectroscopy and measurement of estradiol, progesterone, blood glucose, lactate, free fatty acids (FFA), and insulin concentrations were conducted before exercise (Pre) and immediately after exercise (Post). Muscle glycogen concentrations from thigh muscles at Pre and Post were not significantly different between menstrual cycle phases (P = 0.57). Muscle glycogen decreases by exercise were significantly greater in L-FP (59.0 ± 12.4 mM) than in E-FP (48.3 ± 14.4 mM, P < 0.05). Nonetheless, blood glucose, blood lactate, serum FFA, serum insulin concentrations, and exercise time until exhaustion in E-FP, L-FP, and LP were similar. The study results suggest that although exercise time does not change according to the menstrual cycle, the menstrual cycle influences muscle glycogen utilization during high-intensity intermittent exercise until exhaustion in women with habitual exercise activity. Novelty: This study compared changes in muscle glycogen concentration across the menstrual cycle during high-intensity intermittent exercise until exhaustion using 13C-magnetic resonance spectroscopy. Our results highlight the influence of the menstrual cycle on muscle glycogen during high-intensity intermittent exercise in healthy women.

Keywords:  cycle menstruel; estrogen; exercice intermittent de haute intensité; glycogène musculaire; high-intensity intermittent exercise; hormones ovariennes; late follicular phase; menstrual cycle; muscle glycogen; ovarian hormones; phase folliculaire tardive; œstrogène

DOI:  https://doi.org/10.1139/apnm-2021-0532
Pediatr Nephrol. 2022 Jul 21.

Aggressive immunotherapy combined with bortezomib and rituximab for membranous nephropathy associated with enzyme replacement therapy in Pompe disease.

Keigo Sasaki, Toru Uchimura, Aya Inaba, Masako Otani, Junko Hanakawa, Shuichi Ito.

   BACKGROUND: Pompe disease (PD) is a lysosomal glycogen storage disorder caused by a deficiency in acid α-glucosidase (GAA) activity. Various organs, including the skeletal muscle, cardiac muscle, and liver, are commonly involved. Early initiation of enzyme replacement therapy (ERT) with recombinant human α-glucosidase (rhGAA) can improve the outcome. However, some patients experience a poor clinical course despite ERT because of the emergence of anti-rhGAA antibodies that neutralize rhGAA. Treatment against anti-rhGAA antibodies is challenging.
CASE-DIAGNOSIS/TREATMENT: A 14-year-old boy with late-onset PD was referred to our hospital with proteinuria detected by school urinalysis screening. He was diagnosed with PD at the age of 4 years based on muscle biopsy and decreased GAA activity. Treatment with rhGAA was initiated, but anaphylaxis occurred frequently. Anti-rhGAA antibodies were detected and immune tolerance therapy was therefore given, but his antibody titer remained high. Kidney biopsy revealed stage II membranous nephropathy. Immunohistochemistry staining revealed anti-rhGAA antibody/rhGAA immune complexes along the glomerular capillary loop. Aggressive immunotherapy combined with bortezomib and rituximab was then initiated. Serum levels of anti-rhGAA antibodies decreased significantly and his proteinuria finally resolved.
CONCLUSIONS: There have been few reports of membranous nephropathy associated with ERT for PD. We clarified the cause in the current patient. Bortezomib and rituximab effectively suppressed anti-rhGAA antibody production resulting in the resolution of proteinuria and maintenance of ERT efficacy.

Keywords:  Bortezomib; Child; Enzyme replacement therapy; Membranous nephropathy; Pompe disease; Rituximab

DOI:  https://doi.org/10.1007/s00467-022-05672-5
Nutrition. 2022 Jun 03. pii: S0899-9007(22)00176-9. [Epub ahead of print]103-104 111763

Body composition in patients with hepatic glycogen storage diseases.

Bruna B Dos Santos, Karina Colonetti, Tatiéle Nalin, Bibiana M de Oliveira, Carolina F M de Souza, Poli Mara Spritzer, Ida V D Schwartz.

   OBJECTIVES: The present study aimed to evaluate the body composition of hepatic glycogen storage disorders (GSDs) through dual energy x-ray absorptiometry.
METHODS: This was an exploratory, observational, cross-sectional study. Twenty-four patients with GSD (type Ia: n = 13, Ib: n = 5, III: n = 2, and IX-α/β/γ: n = 4; female sex: n = 13; age <8 y: n = 3, 8-19 y: n = 14, and >19 y: n = 7) were included. Three-day dietary records were collected in the week preceding dual energy x-ray absorptiometry. Body composition findings were correlated with clinical parameters, uncooked cornstarch (UCCS) regimen, dietary intake, and markers of treatment adherence.
RESULTS: An elevated fat mass (FM) index was found in 16 of 21 patients (age 8-19 y: n = 10 and >19 y: n = 6; GSD type Ia: n = 12, Ib: n = 2, III: n = 1, and IX-γ: n = 1). A lean mass (LM) index evaluation showed no LM deficits in relation to corresponding reference populations. Relative skeletal muscle index values were decreased in 2 of 7 adult patients (type Ib: n = 1 and IX-α: n = 1). UCCS (g/d) correlated positively with the FM index (rs = 0.7; P ≤ 0.01). In contrast, relative UCCS intake (g/kg body weight) was negatively associated with LM/kg (rs = -0.8; P ≤ 0.01).
CONCLUSIONS: These findings suggest a high frequency of elevated FM in patients with hepatic GSDs. We also suggest that treatment with UCCS is associated with excess weight in these patients. Additionally, the treatment strategy can impair protein intake, and lead to a decrease in LM.

Keywords:  Body composition; Dual x-ray; Hepatic glycogen storage disease; Inborn errors of metabolism; Uncooked cornstarch; absorptiometry; treatment

DOI:  https://doi.org/10.1016/j.nut.2022.111763
J Biol Chem. 2022 Jul 19. pii: S0021-9258(22)00729-3. [Epub ahead of print] 102287

Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis.

Moritz Oster, Markus Galhuber, Jelena Krstic, Julia S Steinhoff, Georgia Lenihan-Geels, Sascha Wulff, Marie F Kiefer, Konstantin M Petricek, Sylvia J Wowro, Roberto E Flores, Na Yang, Chen Li, Yueming Meng, Isabel Reinisch, Manuela Sommerfeld, Stefan Weger, Hansjörg Habisch, Tobias Madl, Tim J Schulz, Andreas Prokesch, Michael Schupp.

  The tumor suppressor p53 is involved in the adaptation of hepatic metabolism to nutrient availability. Acute deletion of p53 in the mouse liver affects hepatic glucose and triglyceride metabolism. However, long-term adaptations upon the loss of hepatic p53 and its transcriptional regulators are unknown. Here we show that short-term, but not chronic, liver-specific deletion of p53 in mice reduces liver glycogen levels and we implicate the transcription factor forkhead box O1 protein (FOXO1) in the regulation of p53 and its target genes. We demonstrate that acute p53 deletion prevents glycogen accumulation upon refeeding, whereas a chronic loss of p53 associates with a compensational activation of the glycogen synthesis pathway. Moreover, we identify fasting-activated FOXO1 as a repressor of p53 transcription in hepatocytes. We show that this repression is relieved by inactivation of FOXO1 by insulin, which likely mediates the upregulation of p53 expression upon refeeding. Strikingly, we find that high fat diet-induced insulin resistance with persistent FOXO1 activation not only blunted the regulation of p53 but also the induction of p53 target genes like p21 during fasting, indicating overlapping effects of both FOXO1 and p53 on target gene expression in a context-dependent manner. Thus, we conclude that p53 acutely controls glycogen storage in the liver and is linked to insulin signaling via FOXO1, which has important implications for our understanding of the hepatic adaptation to nutrient availability.

Keywords:  Foxo1; fasting; glucose metabolism; glycogen; liver; p53; triglycerides

DOI:  https://doi.org/10.1016/j.jbc.2022.102287