bims-glecem 2023-11-19 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–11–19
nine papers selected by
Dipsikha Biswas, Københavns Universitet

GSK3 as a Master Regulator of Cellular Processes.
Savory Cracker Development for Blood Glucose Control and Management: Glycogen Storage Diseases.
Late-Onset Pompe Disease with Normal Creatine Kinase Levels: The Importance of Rheumatological Suspicion.
Critical Velocity, Maximal Lactate Steady State, and Muscle MCT1 and MCT4 after Exhaustive Running in Mice.
Cooling of male rat skeletal muscle during endurance-like contraction attenuates contraction-induced PGC-1α mRNA expression.
Glycogen synthase kinase 3 inhibition enhances mineral nodule formation by cementoblasts in vitro.
Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes.
Locomotor and respiratory muscle abnormalities in HFrEF and HFpEF.
Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance.

Int J Mol Sci. 2023 Oct 24. pii: 15503. [Epub ahead of print]24(21):

GSK3 as a Master Regulator of Cellular Processes.

Ralf Lichtinghagen, René Huber.

Since its initial purification and characterization as an enzyme negatively regulating glycogen synthase activity [...].

DOI: https://doi.org/10.3390/ijms242115503
J Med Food. 2023 Nov 15.

Savory Cracker Development for Blood Glucose Control and Management: Glycogen Storage Diseases.

Xin Qi, Minh N Ta, Richard F Tester.

  The blood glucose response of savory slow energy-release crackers (GLY-HYP) were evaluated in volunteers carrying glycogen storage diseases (GSDs), Types I (Ia) and IV. The crackers have been shown previously to provide a "flat" slow glucose response in healthy volunteers, for up to 4 h. On average for the mixed-sex volunteer group aged 53 to 70 for Type I, the blood glucose concentration increased from baseline to a maximum of 9.5 mmol/L at 60 min and remained above baseline for up to 210 min; overall, above 5 mmol/L for 4 h. In common with healthy individuals, a relatively flat blood glucose response was recorded. For Type IV, mixed-sex patients aged between 55 and 72, the blood glucose concentration reached maximum of 10.2 mmol/L at 45 min and then stayed above baseline for 150 min. Again, overall, above 5 mmol/L for 4 h. Altogether, these data indicate that these crackers would provide a valuable contribution to the nutritional needs of people of different age groups with GSDs (Clinical Registration Number: HRC10032021).

Keywords:  blood glucose; glycogen storage diseases; hyperglycemia management; hypoglycemia management

DOI:  https://doi.org/10.1089/jmf.2023.0165
Int J Mol Sci. 2023 Nov 03. pii: 15924. [Epub ahead of print]24(21):

Late-Onset Pompe Disease with Normal Creatine Kinase Levels: The Importance of Rheumatological Suspicion.

Daniela Marotto, Marta Moschetti, Alessia Lo Curto, Anna M Spezzigu, Miriam Giacomarra, Emanuela M Marsana, Carmela Zizzo, Giovanni Duro, Paolo Colomba.

  Pompe disease (PD), also defined as acid maltase deficiency, is a rare autosomal recessive disease that causes glycogen accumulation due to a deficiency of the lysosomal enzyme acid α-glucosidase. An excessive amount of undisposed glycogen causes progressive muscle weakness throughout the body. It particularly affects skeletal muscles and the nervous system, especially in the late-onset phase. Here, we present a clinical case of late-onset PD (LOPD) with normal CK (creatinine kinase) values treated after a misdiagnosis of demyelinating motor polyneuropathy and chronic inflammatory neuropathy. The suspicion of possible fibromyalgia induced the patient to seek a rheumatology consultation, and the investigations performed led to the diagnosis of PD. The patient was investigated for genetic and enzymatic studies. PD was diagnosed using the α-glucosidase assay on DBS. In LOPD, clinical manifestations, such as muscle weakness, exercise intolerance, myalgia, or even high hyperCKemia, often appear as nonspecific and may mimic a wide variety of other muscle disorders, such as limb muscle dystrophies, congenital, metabolic, or inflammatory myopathies. In our case, the patient had CK values in the normal range but with continued complaints typical of PD. An analysis of enzyme activity revealed a pathologic value, and genetic analysis identified the c.-32-13T>G mutation in homozygosis. The association of the pathological enzyme value and mutation in homozygosity with LOPD led to a familial segregation study. Our results contribute to the characterization of PD in Italy and support the importance of rheumatologic attention. This suggests further studies are needed to define the broad clinical and pathological spectrum observed in this disease.

Keywords:  Late Onset Pompe Disease; creatinine kinase value; metabolic myopathy; misdiagnosis

DOI:  https://doi.org/10.3390/ijms242115924
Int J Mol Sci. 2023 Oct 30. pii: 15753. [Epub ahead of print]24(21):

Critical Velocity, Maximal Lactate Steady State, and Muscle MCT1 and MCT4 after Exhaustive Running in Mice.

Juan B Orsi, Lara S Araujo, Pedro P M Scariot, Emanuel E C Polisel, Luisa O Cardoso, Claudio A Gobatto, Fúlvia B Manchado-Gobatto.

  Although the critical velocity (CV) protocol has been used to determine the aerobic capacity in rodents, there is a lack of studies that compare CV with maximal lactate steady state intensity (iMLSS) in mice. As a consequence, their physiological and molecular responses after exercise until exhaustion at CV intensity remain unclear. Thus, we aimed to compare and correlate CV with iMLSS in running mice, following different mathematical models for CV estimation. We also evaluated their physiological responses and muscle MCT1 and MCT4 after running until exhaustion at CV. Thirty C57BL/6J mice were divided into two groups (exercised-E and control-C). Group E was submitted to a CV protocol (4 days), using linear (lin1 and lin2) and hyperbolic (hyp) mathematical models to determine the distance, velocity, and time to exhaustion (tlim) of each predictive CV trial, followed by an MLSS protocol. After a running effort until exhaustion at CV intensity, the mice were immediately euthanized, while group C was euthanized at rest. No differences were observed between iMLSS (21.1 ± 1.1 m.min-1) and CV estimated by lin1 (21.0 ± 0.9 m.min-1, p = 0.415), lin2 (21.3 ± 0.9 m.min-1, p = 0.209), and hyp (20.6 ± 0.9 m.min-1, p = 0.914). According to the results, CV was significantly correlated with iMLSS. After running until exhaustion at CV (tlim = 28.4 ± 8,29 min), group E showed lower concentrations of hepatic and gluteal glycogen than group C, but no difference in the content of MCT1 (p = 0.933) and MCT4 (p = 0.123) in soleus muscle. Significant correlations were not found between MCT1 and MCT4 and tlim at CV intensity. Our results reinforce that CV is a valid and non-invasive protocol to estimate the maximal aerobic capacity in mice and that the content of MCT1 and MCT4 was not decisive in determining the tlim at CV, at least when measured immediately after the running effort.

Keywords:  aerobic capacity; blood lactate; mathematical models; monocarboxylate transporters; physiological parameters; running mice

DOI:  https://doi.org/10.3390/ijms242115753
Physiol Rep. 2023 Nov;11(21): e15867

Cooling of male rat skeletal muscle during endurance-like contraction attenuates contraction-induced PGC-1α mRNA expression.

Daisuke Hoshino, Ryota Wada, Yutaro Mori, Reo Takeda, Yudai Nonaka, Ryotaro Kano, Ryo Takagi, Yutaka Kano.

  This study aimed to determine effects of cooling on contraction-induced peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and vascular endothelial growth factor (VEGF) gene expression, phosphorylations of its related protein kinases, and metabolic responses. Male rats were separated into two groups; room temperature (RT) or ice-treated (COLD) on the right tibialis anterior (TA). The TA was contracted isometrically using nerve electrical stimulation (1-s stimulation × 30 contractions, with 1-s intervals, for 10 sets with 1-min intervals). The TA was treated before the contraction and during 1-min intervals with an ice pack for the COLD group and a water pack at RT for the RT group. The muscle temperature of the COLD group decreased to 19.42 ± 0.44°C (p < 0.0001, -36.4%) compared with the RT group after the experimental protocol. An increase in mRNA expression level of PGC-1α, not VEGF, after muscle contractions was significantly lower in the COLD group than in the RT group (p < 0.0001, -63.0%). An increase in phosphorylated AMP-activated kinase (AMPK) (p = 0.0037, -28.8%) and a decrease in glycogen concentration (p = 0.0231, +106.3%) after muscle contraction were also significantly inhibited by cooling. Collectively, muscle cooling attenuated the post-contraction increases in PGC-1α mRNA expression coinciding with decreases in AMPK phosphorylation and glycogen degradation.

Keywords:  glycogen; lactate; signal molecules; temperature

DOI:  https://doi.org/10.14814/phy2.15867
Braz Oral Res. 2023 ;pii: S1806-83242023000100294. [Epub ahead of print]37 e112

Glycogen synthase kinase 3 inhibition enhances mineral nodule formation by cementoblasts in vitro.

Henrique Abdalla, Rafael Storino, Amanda Bandeira, Lucas Teixeira, Ana Millás, Paulo Lisboa-Filho, Kamila Kantovitz, Francisco Nociti Junior.

This study aimed to investigate whether GSK-3 inhibition (CHIR99021) effectively promoted mineralization by cementoblasts (OCCM-30). OCCM-30 cells were used and treated with different concentrations of CHIR99021 (2.5, 5, and 10 mM). Experiments included proliferation and viability, cellular metabolic activity, gene expression, and mineral nodule formation by Xylene Orange at the experimental time points. In general, CHIR99021 did not significantly affect OCCM-30 viability and cell metabolism (MTT assay) (p > 0.05), but increased OCCM-30 proliferation at 2.5 mM on days 2 and 4 (p < 0.05). Data analysis further showed that inhibition of GSK-3 resulted in increased transcript levels of Axin2 in OCCM-30 cells starting as early as 4 h, and regulated the expression of key bone markers including alkaline phosphatase (Alp), runt-related transcription factor 2 (Runx-2), osteocalcin (Ocn), and osterix (Osx). In addition, CHIR99021 led to an enhanced mineral nodule formation in vitro under both osteogenic and non-osteogenic conditions as early as 5 days after treatment. Altogether, the results of the current study suggest that inhibition of GSK-3 has the potential to promote cementoblast differentiation leading to increased mineral deposition in vitro.

DOI: https://doi.org/10.1590/1807-3107bor-2023.vol37.0112
Mol Neurobiol. 2023 Nov 16.

Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes.

Teresa Rubio, Ángela Campos-Rodríguez, Pascual Sanz.

  Lafora disease (LD; OMIM#254780) is a rare, devastating, and fatal form of progressive myoclonus epilepsy that affects young adolescents and has no treatment yet. One of the hallmarks of the disease is the accumulation of aberrant poorly branched forms of glycogen (polyglucosans, PGs) in the brain and peripheral tissues. The current hypothesis is that this accumulation is causative of the pathophysiology of the disease. Another hallmark of LD is the presence of neuroinflammation. We have recently reported the presence of reactive glia-derived neuroinflammation in LD mouse models and defined the main inflammatory pathways that operate in these mice, mainly TNF and IL-6 signaling pathways. In addition, we described the presence of infiltration of peripheral immune cells in the brain parenchyma, which could cooperate and aggravate the neuroinflammatory landscape of LD. In this work, we have checked the beneficial effect of two compounds with the capacity to ameliorate neuroinflammation and reduce leukocyte infiltration into the brain, namely fingolimod and dimethyl fumarate. Our results indicate a beneficial effect of fingolimod in reducing reactive astrogliosis-derived neuroinflammation and T-lymphocyte infiltration, which correlated with the improved behavioral performance of the treated Epm2b-/- mice. On the contrary, dimethyl fumarate, although it was able to reduce reactive astrogliosis, was less effective in preventing neuroinflammation and T-lymphocyte infiltration and in modifying behavioral tests.

Keywords:  Dimethyl fumarate; Fingolimod; Lafora disease; Neuroinflammation; T-lymphocyte infiltration

DOI:  https://doi.org/10.1007/s12035-023-03766-1
Front Cardiovasc Med. 2023 ;10 1149065

Locomotor and respiratory muscle abnormalities in HFrEF and HFpEF.

Norman Mangner, Ephraim B Winzer, Axel Linke, Volker Adams.

  Heart failure (HF) is a chronic and progressive syndrome affecting worldwide billions of patients. Exercise intolerance and early fatigue are hallmarks of HF patients either with a reduced (HFrEF) or a preserved (HFpEF) ejection fraction. Alterations of the skeletal muscle contribute to exercise intolerance in HF. This review will provide a contemporary summary of the clinical and molecular alterations currently known to occur in the skeletal muscles of both HFrEF and HFpEF, and thereby differentiate the effects on locomotor and respiratory muscles, in particular the diaphragm. Moreover, current and future therapeutic options to address skeletal muscle weakness will be discussed focusing mainly on the effects of exercise training.

Keywords:  HFpEF; HFrEF; cachexia; diaphragm; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3389/fcvm.2023.1149065
JCI Insight. 2023 Nov 14. pii: e172549. [Epub ahead of print]

Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance.

Omprakash Singh, Sean B Ogden, Salil Varshney, Kripa Shankar, Deepali Gupta, Subhojit Paul, Sherri Osborne-Lawrence, Corine P Richard, Nathan P Metzger, Connor Lawrence, Luis León-Mercado, Jeffrey M Zigman.

  Previous studies have implicated the orexigenic hormone ghrelin as a mediator of exercise endurance and the feeding response post-exercise. Specifically, plasma ghrelin levels nearly double in mice when they are submitted to an hour-long bout of high-intensity interval exercise (HIIE) using treadmills. Also, GHSR (ghrelin receptor)-null mice exhibit decreased food intake following HIIE and a diminished running distance (time until exhaustion) during a longer, step-wise exercise endurance protocol. To investigate whether ghrelin-responsive mediobasal hypothalamus (MBH) neurons mediate these effects, we stereotaxically delivered the inhibitory DREADD virus AAV2-hSyn-DIO-hM4(Gi)-mCherry to the MBH of Ghsr-IRES-Cre mice, which express Cre-recombinase directed by the Ghsr promoter. We found that chemogenetic inhibition of GHSR-expressing MBH neurons [upon delivery of clozapine-N-oxide (CNO)] 1) suppressed food intake following HIIE by 31.3%, 2) reduced maximum running distance by 20.7%-22.7% and raised blood glucose and blood lactate levels by 18.4%-51.5% and 24.6%-39.2%, respectively, during an exercise endurance protocol, 3) reduced food intake following ghrelin administration by 57.2%, but 4) did not affect glucose tolerance. Further, HIIE increased MBH Ghsr expression. These results indicate that activation of ghrelin-responsive MBH neurons is required for the normal feeding response to HIIE and the usual amount of running exhibited during an exercise endurance protocol.

Keywords:  G proteincoupled receptors; Metabolism; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.172549