bims-glecem 2023-12-10 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–12–10
eight papers selected by
Dipsikha Biswas, Københavns Universitet

Periportal hepatocyte proliferation at midgestation governs maternal glucose homeostasis in mice.
Assessing exogenous carbohydrate intake needed to optimize human endurance performance across sex: Insights from modeling runners pursuing a sub-2-hour marathon.
Glycogen synthase kinase 3 signaling in neural regeneration in vivo.
Fatigue and associated factors in 172 patients with McArdle disease: An international web-based survey.
[Infant glycogen storage disease type Ⅳ: a clinicopathological and genetic characteristics analysis of five cases].
Diagnostic accuracy and the first genotype-phenotype correlation in glycogen storage disease type V.
Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).
Long-Term Outcome of Infantile Onset Pompe Disease Patients Treated with Enzyme Replacement Therapy - Data from a German-Austrian Cohort.

Commun Biol. 2023 Dec 04. 6(1): 1226

Periportal hepatocyte proliferation at midgestation governs maternal glucose homeostasis in mice.

Satoshi Kozuki, Mio Kabata, Satoko Sakurai, Keiko Iwaisako, Tomomi Nishimura, Masakazu Toi, Takuya Yamamoto, Fumiko Toyoshima.

The maternal liver is challenged by metabolic demands throughout pregnancy. However, hepatocyte dynamics and their physiological significance in pregnancy remain unclear. Here, we show in mice that hepatocyte proliferation is spatiotemporally regulated in each liver lobular zone during pregnancy, with transient proliferation of periportal and pericentral hepatocytes during mid and late gestation, respectively. Using adeno-associated virus (AAV)-8-mediated expression of the cell cycle inhibitor p21 in hepatocytes, we show that inhibition of hepatocyte proliferation during mid, but not late, gestation impairs liver growth. Transcriptionally, genes involved in glucose/glycogen metabolism are downregulated in late pregnancy when midgestational hepatocyte proliferation is attenuated. In addition, hepatic glycogen storage is abolished, with concomitant elevated blood glucose concentrations, glucose intolerance, placental glycogen deposition, and fetal overgrowth. Laser capture microdissection and RNA-seq analysis of each liver lobular zone show zone-specific changes in the transcriptome during pregnancy and identify genes that are periportally expressed at midgestation, including the hyaluronan-mediated motility receptor (Hmmr). Knockdown of Hmmr in hepatocytes by AAV8-shHmmr suppresses periportal hepatocyte proliferation at midgestation and induces impaired hepatic glycogen storage, glucose intolerance, placental glycogen deposition and fetal overgrowth. Our results suggest that periportal hepatocyte proliferation during midgestation is critical for maternal glycogen metabolism and fetal size.

DOI: https://doi.org/10.1038/s42003-023-05614-3
J Appl Physiol (1985). 2023 Dec 07.

Assessing exogenous carbohydrate intake needed to optimize human endurance performance across sex: Insights from modeling runners pursuing a sub-2-hour marathon.

Cole J Lukasiewicz, Kayla J Vandiver, Elizabeth D Albert, Brett S Kirby, Robert A Jacobs.

   INTRODUCTION: Carbohydrate (CHO) availability sustains high metabolic demands during prolonged exercise. The adequacy of current CHO intake recommendations, 30-90 g•hr-1 dependent on CHO mixture and tolerability, to support elite marathon performance is unclear.
PURPOSE: We sought to scrutinize the current upper limit recommendation for exogenous CHO intake to support modeled sub-2-hour marathon (S2M) attempts across elite male and female runners.
METHODS: Male and female runners (n = 120 each) were modeled from published literature with reference characteristics necessary to complete a S2M (e.g., body mass and running economy). Completion of a S2M was considered across a range of respiratory exchange rates, with maximal starting skeletal muscle and liver glycogen content predicted for elite male and female runners.
RESULTS: Modeled exogenous CHO bioavailability needed for male and female runners were 93 ± 26 and 108 ± 22 g•h-1, respectively (p < 0.0001, d = 0.61). Without exogenous CHO, males were modeled to deplete glycogen in 84 ± 7 minutes, females in 71 ± 5 minutes (p < 0.0001, d = 2.21) despite higher estimated CHO oxidation rates in males (5.1 ± 0.5 g•h-1) than females (4.4 ± 0.5 g•h-1; p < 0.0001, d = 1.47).
CONCLUSION: Exogenous CHO intakes < 90 g•h-1 are insufficient for 65% of modeled runners attempting a S2M. Current recommendations to support marathon performance appear inadequate for elite marathon runners but may be more suitable for male runners in pursuit of a S2M (56 of 120) than female runners (28 of 120).

Keywords:  carbohydrate; glycogen; metabolism; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00521.2023
J Mol Cell Biol. 2023 Dec 06. pii: mjad075. [Epub ahead of print]

Glycogen synthase kinase 3 signaling in neural regeneration in vivo.

Jing Zhang, Shu-Guang Yang, Feng-Quan Zhou.

  Glycogen synthase kinase 3 (GSK3) signaling plays important and broad roles in regulating neural development in vitro and in vivo. Here, we reviewed recent findings of GSK3-regulated axon regeneration in vivo in both the peripheral and central nervous systems and discussed a few controversial findings in the field. Overall, current evidence indicates that GSK3β signaling serves as an important downstream mediator of the PI3K-AKT pathway to regulate axon regeneration in parallel with the mTORC1 pathway. Specifically, the mTORC1 pathway supports axon regeneration mainly through its role in regulating cap-dependent protein translation, whereas GSK3β signaling might be involved in regulating N6-methyladenosine (m6A) mRNA methylation-mediated cap-independent protein translation. In addition, GSK3 signaling also plays key roles in reshaping the neuronal transcriptomic landscape during neural regeneration. Finally, we proposed some research directions to further elucidate the molecular mechanisms underlying the regulatory function of GSK3 signaling and discover novel GSK3 signaling-related therapeutic targets. Together, we hope to provide an updated and insightful overview of how GSK3 signaling regulates neural regeneration in vivo.

Keywords:  GSK3; gene transcription; neural regeneration; protein translation

DOI:  https://doi.org/10.1093/jmcb/mjad075
Neuromuscul Disord. 2023 Nov 11. pii: S0960-8966(23)00792-7. [Epub ahead of print]

Fatigue and associated factors in 172 patients with McArdle disease: An international web-based survey.

Anna Slipsager, Linda Kahr Andersen, Nicol Cornelia Voermans, Alejandro Lucia, Walaa Karazi, Alfredo Santalla, John Vissing, Nicoline Løkken.

  McArdle disease is an autosomal recessive inherited disease caused by pathogenic variants in the PYGM gene, resulting in virtual absence of the myophosphorylase enzyme in skeletal muscle. Patients experience physical activity intolerance, muscle pain, and muscle fatigue. This study aimed to investigate other fatigue domains with the Multidimensional Fatigue Inventory (MFI-20) along with an investigation of potential contributing factors, including relevant disease and lifestyle-related factors. We conducted a survey in an international cohort of patients with McArdle disease. The survey included questions on demographics and McArdle disease-related symptoms, and the questionnaires: MFI-20, Insomnia Severity Index (ISI), and International Physical Activity Questionnaire Short-Form (IPAQ-SF). One hundred seventy-four responses were included in the data analyses. We found relatively high fatigue scores in all five domains (general fatigue (12.9 ± 2.2), mental fatigue (10.1 ± 4.1), physical fatigue (13.7 ± 4.1), reduced activity (12.1 ± 4.1), and reduced motivation (10.4 ± 3.4)). Fatigue associated with McArdle symptom severity (p < 0.005), lower levels of physical activity (assessed by IPAQ-SF) (p < 0.05), and poor sleep (assessed by ISI) (p < 0.05). These findings call for clinical focus and future research into fatigue, sleep and mental health in patients with McArdle disease.

Keywords:  Fatigue; Glycogen storage disease type V; McArdle disease; Mental health; Survey

DOI:  https://doi.org/10.1016/j.nmd.2023.11.003
Zhonghua Bing Li Xue Za Zhi. 2023 Dec 08. 52(12): 1255-1260

[Infant glycogen storage disease type Ⅳ: a clinicopathological and genetic characteristics analysis of five cases].

Q Y Wang, J S Wang, L Chen.

Objective: To investigate the clinical pathology and gene mutation characteristics of patients with glycogen storage disease type Ⅳ (GSD Ⅳ). Methods: The clinical data, liver histopathology and ultrastructural morphology, and gene sequencing results of 5 GSD Ⅳ cases diagnosed in the Children's Hospital Affiliated to Shanghai Jiaotong University School of Medicine and the Children's Hospital of Fudan University from January 2015 to February 2022 were collected and analyzed retrospectively. Results: Among the 5 cases, 3 were male and 2 were female, ranging in age from 4 months to 1 year and 9 months. The clinical manifestations included fever, hepatosplenomegaly, liver insufficiency, growth retardation and hypotonia. Four cases had liver biopsy showing ground-glass-like changes in hepatocytes with intracytoplasmic inclusion bodies and varying degrees of fibrosis. Liver electron microscopy in 2 cases showed that the level of glycogen increased to varying degrees, and the cytoplasm was filled with low electron density substances. Genetic testing revealed that 3 cases had compound heterozygous variants in GBE1 gene; 1 case had a single pathogenic variant in GBE1 gene; and 1 case was deceased with no genetic testing, but each parent was tested for a heterozygous variant in the GBE1 gene. A total of 9 GBE1 gene mutations were detected, 3 of which were reported mutations and 6 novel mutations. One case died of liver cirrhosis, and 1 case underwent autologous liver transplantation. After transplantation, the liver function basically returned to normal, and the growth and development improved; the other 3 cases were managed through diet control and symptomatic treatment. Conclusions: CSD Ⅳ is an extremely rare inherited metabolic disease caused by GBE1 gene mutation, often presenting with hepatic and neuromuscular disorders, with heterogeneous clinical manifestations. The diagnosis mainly depends on histopathology and a pedigree gene analysis.

DOI: https://doi.org/10.3760/cma.j.cn112151-20230727-00032
Pediatr Res. 2023 Dec 05.

Diagnostic accuracy and the first genotype-phenotype correlation in glycogen storage disease type V.

Jorge Diogo Da Silva, Ângela Pereira, Ana Rita Soares, Arlindo Guimas, Sara Rocha, Márcio Cardoso, Cristina Garrido, Célia Azevedo Soares, Isabel Serra Nunes, Ana Maria Fortuna, Dulce Quelhas, Sónia Figueiroa, Rosa Ribeiro, Manuela Santos, Esmeralda Martins, Nataliya Tkachenko.

BACKGROUND: Glycogen storage disease type V (GSDV) is an autosomal recessive metabolic condition caused by pathogenic PYGM variants. This is an underdiagnosed condition as it presents with exercise intolerance in children. We reviewed the GSDV cases of a tertiary hospital center to assess diagnostic timing/accuracy, as well as potential clinical/analytical predictors of such factors.
METHODS: We retrospectively reviewed all GSDV cases with follow-up in both Pediatric and Adult Metabolic Diseases consultations. We included 28 cases and assessed their hospital record for clinical information.
RESULTS: Over 90% of our cases had late diagnoses, with more than 50% being diagnosed in adulthood despite symptom onset in preschool (very late diagnosis). Diagnostic age was lower in patients exhibiting myoglobinuria. Interestingly, patients with a positive family history of GSDV had similar rates of very late diagnoses, likely since the index case was already detected very late in life. Finally, we observe that the R50* variant is associated with increased myoglobinuria and CK elevation, in a dosage-dependent manner.
CONCLUSION: We concluded that GSDV is severely underdiagnosed, and that some clinical and analytical aspects of the condition can be more indicative of this diagnosis. Furthermore, we propose for the first time a genotype-phenotype correlation in GSDV.
IMPACT: GSDV is a pediatric-onset metabolic disorder that is mostly diagnosed late in the adult age and commonly misdiagnosed. We observed the first genotype-phenotype correlation in GSDV, regarding the common R50* variant. Awareness of GSDV for pediatricians and the overall medical community is vital.

DOI: https://doi.org/10.1038/s41390-023-02943-1
J Neurol. 2023 Dec 06.

Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).

Barry J Byrne, Benedikt Schoser, Priya S Kishnani, Drago Bratkovic, Paula R Clemens, Ozlem Goker-Alpan, Xue Ming, Mark Roberts, Matthias Vorgerd, Kumaraswamy Sivakumar, Ans T van der Ploeg, Mitchell Goldman, Jacquelyn Wright, Fred Holdbrook, Vipul Jain, Elfrida R Benjamin, Franklin Johnson, Sheela Sitaraman Das, Yasmine Wasfi, Tahseen Mozaffar.

  Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Keywords:  Alpha glucosidases; Glycogen storage disease type II; Lysosomal storage diseases; Myozyme; Pharmacokinetics; n-Butyldeoxynojirimycin

DOI:  https://doi.org/10.1007/s00415-023-12096-0
J Neuromuscul Dis. 2023 Nov 27.

Long-Term Outcome of Infantile Onset Pompe Disease Patients Treated with Enzyme Replacement Therapy - Data from a German-Austrian Cohort.

Charlotte Pfrimmer, Martin Smitka, Nicole Muschol, Ralf A Husain, Martina Huemer, Julia B Hennermann, Rahel Schuler, Andreas Hahn.

   BACKGROUND: Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) was approved in Europe in 2006. Nevertheless, data on the long-term outcome of infantile onset Pompe disease (IOPD) patients at school age is still limited.
OBJECTIVE: We analyzed in detail cardiac, respiratory, motor, and cognitive function of 15 German-speaking patients aged 7 and older who started ERT at a median age of 5 months.
RESULTS: Starting dose was 20 mg/kg biweekly in 12 patients, 20 mg/kg weekly in 2, and 40 mg/kg weekly in one patient. CRIM-status was positive in 13 patients (86.7%) and negative or unknown in one patient each (6.7%). Three patients (20%) received immunomodulation. Median age at last assessment was 9.1 (7.0-19.5) years. At last follow-up 1 patient (6.7%) had mild cardiac hypertrophy, 6 (42.9%) had cardiac arrhythmias, and 7 (46.7%) required assisted ventilation. Seven patients (46.7%) achieved the ability to walk independently and 5 (33.3%) were still ambulatory at last follow-up. Six patients (40%) were able to sit without support, while the remaining 4 (26.7%) were tetraplegic. Eleven patients underwent cognitive testing (Culture Fair Intelligence Test), while 4 were unable to meet the requirements for cognitive testing. Intelligence quotients (IQs) ranged from normal (IQ 117, 102, 96, 94) in 4 patients (36.4%) to mild developmental delay (IQ 81) in one patient (9.1%) to intellectual disability (IQ 69, 63, 61, 3x <55) in 6 patients (54.5%). White matter abnormalities were present in 10 out of 12 cerebral MRIs from 7 patients.
CONCLUSION: Substantial motor, cardiac, respiratory, and cognitive deficits are frequent in IOPD long-term survivors who started ERT before 2016. The findings of this study can be valuable as comparative data when evaluating the impact of newer treatment strategies including higher enzyme dosage, immunomodulation, modified enzymes, or early start of treatment following newborn screening.

Keywords:  Infantile onset Pompe disease; long-term outcome; prognosis

DOI:  https://doi.org/10.3233/JND-230164