bims-glecem 2023-12-03 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–12–03
fiveteen papers selected by
Dipsikha Biswas, Københavns Universitet

In vivo characterization of glycogen storage disease type III in a mouse model using glycoNOE MRI.
Muscle glycogen depletion: a weak-link rendering muscle cells prone to potassium-induced fatigue?
Clinical Remission of Severe Crohn's Disease with Empagliflozin Monotherapy in a Pediatric Patient with Glycogen Storage Disease Type 1b.
A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III.
Glycogen Storage Disease Type I With Hypercalcemia in an Infant: A Case Report.
Severe neuromuscular forms of glycogen storage disease type IV: Histological, clinical, biochemical, and molecular findings in a large French case series.
Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability: Insights from McArdle disease.
Liver Biopsy Leads to Serendipitous Diagnosis of Glycogen Storage Disease Type IX in a Patient With Fontan-Associated Liver Disease.
Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer's Disease.
Mutational analysis and clinical investigations of medically diagnosed GSD 1a patients from Pakistan.
Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder.
Glucoregulatory effect of butyrate is associated with elevated circulating VEGF and reduced cardiac lactate in high fructose fed rats.
Glycogen synthase kinase-3β mediates toll-like receptors 4/nuclear factor kappa-B-activated cerebral ischemia-reperfusion injury through regulation of fat mass and obesity-associated protein.
Skeletal muscle-specific inducible AMPKα1/α2 knockout mice develop muscle weakness, glycogen depletion, and fibrosis that persists during disuse atrophy.
Lack of vitamin D signalling shifts skeletal muscles towards oxidative metabolism.

Magn Reson Med. 2023 Nov 27.

In vivo characterization of glycogen storage disease type III in a mouse model using glycoNOE MRI.

Qing Zeng, Michael Machado, Chongxue Bie, Peter C M van Zijl, Sofi Malvar, Yuguo Li, Valentina D'souza, Kirsten Achilles Poon, Andrew Grimm, Nirbhay N Yadav.

   PURPOSE: Glycogen storage disease type III (GSD III) is a rare inherited metabolic disease characterized by excessive accumulation of glycogen in liver, skeletal muscle, and heart. Currently, there are no widely available noninvasive methods to assess tissue glycogen levels and disease load. Here, we use glycogen nuclear Overhauser effect (glycoNOE) MRI to quantify hepatic glycogen levels in a mouse model of GSD III.
METHODS: Agl knockout mice (n = 13) and wild-type controls (n = 10) were scanned for liver glycogen content using glycoNOE MRI. All mice were fasted for 12 to 16 h before MRI scans. GlycoNOE signal was quantified by fitting the Z-spectrum using a four-pool Voigt lineshape model. Next, the fitted direct water saturation pool was removed and glycoNOE signal was estimated from the integral of the residual Z spectrum within -0.6 to -1.4 ppm. Glycogen concentration was also measured ex vivo using a biochemical assay.
RESULTS: GlycoNOE MRI clearly distinguished Agl knockout mice from wild-type controls, showing a statistically significant difference in glycoNOE signals in the livers across genotypes. There was a linear correlation between glycoNOE signal and glycogen concentration determined by the biochemical assay. The obtained glycoNOE maps of mouse livers also showed higher glycogen levels in Agl knockout mice compared to wild-type mice.
CONCLUSION: GlycoNOE MRI was used successfully as a noninvasive method to detect liver glycogen levels in mice, suggesting the potential of this method to be applied to assess glycogen storage diseases.

Keywords:  glycogen; glycogen storage disease type III; liver; saturation transfer

DOI:  https://doi.org/10.1002/mrm.29923
J Physiol. 2023 Dec 02.

Muscle glycogen depletion: a weak-link rendering muscle cells prone to potassium-induced fatigue?

Jeppe F Vigh-Larsen.



Keywords:  carbohydrate; excitability; intermittent exercise; metabolism

DOI:  https://doi.org/10.1113/JP285818
JPGN Rep. 2023 Nov;4(4): e356

Clinical Remission of Severe Crohn's Disease with Empagliflozin Monotherapy in a Pediatric Patient with Glycogen Storage Disease Type 1b.

Lauren V Collen, Peter E Newburger, Scott B Snapper.

  Glycogen storage disease type 1b (GSD1b) is associated with inflammatory bowel disease and congenital neutropenia. Neutropenia in GSD1b is caused by the accumulation of 1,5-anhydroglucitol-6-phosphate. Empagliflozin is an antidiabetic drug that promotes renal excretion of this metabolite. We report on a patient with refractory GSD1b-associated inflammatory bowel disease who is in clinical remission on empagliflozin monotherapy.

Keywords:  Crohn’s disease; SGLT2 inhibitor; empagliflozin; glycogen storage disease; inflammatory bowel disease; precision medicine; very early onset inflammatory bowel disease

DOI:  https://doi.org/10.1097/PG9.0000000000000356
J Clin Invest. 2023 Nov 28. pii: e172018. [Epub ahead of print]

A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III.

Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, Romain Launay, Mallaury Vie, Youssef Krimi Benchekroun, Jérémie Cosette, Bérangère Bertin, Tiziana La Bella, Guillaume Dubreuil, Justine Nozi, Louisa Jauze, Romain Fragnoud, Nathalie F Daniele, Laetitia Van Wittenberghe, Jérémy Esque, Isabelle André, Xavier Nissan, Lucile Hoch, Giuseppe Ronzitti.

  Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus (rAAV)-derived vector gene therapy strategy. Using information on GDE structure and molecular modeling, we generated multiple truncated GDEs retaining activity. Among them, an N-terminal-truncated mutant ∆Nter2-GDE had a similar efficacy in vivo compared to the full-size enzyme. A rAAV vector expressing ∆Nter2-GDE allowed significant glycogen reduction in heart and muscle of Agl-/- mice three months after intravenous injection, as well as normalization of histology features and restoration of muscle strength. Similarly, glycogen accumulation and histological features were corrected in a recently generated Agl-/- rat model. Finally, transduction with rAAV vectors encoding ∆Nter2-GDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of GSDIII. In conclusion, our results demonstrated the ability of a single rAAV vector expressing a functional mini-GDE transgene to correct the muscle and heart phenotype in multiple models of GSDIII, supporting its clinical translation to GSDIII patients.

Keywords:  Carbohydrate metabolism; Gene therapy; Metabolism; Neuromuscular disease; Therapeutics

DOI:  https://doi.org/10.1172/JCI172018
Cureus. 2023 Oct;15(10): e46987

Glycogen Storage Disease Type I With Hypercalcemia in an Infant: A Case Report.

Aziza Elouali, Chaimae N'joumi, Amal Bennani, Maria Rkain, Abdeladim Babakhouya.

  Glycogen storage disease type I (GSDI) is an uncommon condition resulting from a deficiency or absence of glucose-6-phosphatase, a key enzyme in regulating blood glucose levels. In this report, we describe a two-month-old girl diagnosed with GSDI who presented to the emergency department in a tertiary care hospital for irritability, excessive crying, and hyperventilation. She was found to have hepatomegaly and hypoglycemia. Laboratory investigations showed high levels of triglycerides, lactic acid, uric acid, and calcium. The combination of hypertriglyceridemia, hypoglycemia, and hepatomegaly should alert neonatologists and pediatricians to consider GSDI in the diagnosis. Hypercalcemia arose as an unknown problem in GSDI patients and should be considered during acute attacks.

Keywords:  case report; glycogen storage disease; glycogen storage disease type i; hypercalcemia; hypertriglyceridemia; metabolic decompensation

DOI:  https://doi.org/10.7759/cureus.46987
J Inherit Metab Dis. 2023 Nov 27.

Severe neuromuscular forms of glycogen storage disease type IV: Histological, clinical, biochemical, and molecular findings in a large French case series.

Charles R Lefèvre, Sophie Collardeau-Frachon, Nathalie Streichenberger, Sophie Berenguer-Martin, Alix Clémenson, Jérôme Massardier, Fabienne Prieur, Hélène Laurichesse, Fanny Laffargue, Cécile Acquaviva-Bourdain, Roseline Froissart, Magali Pettazzoni.

  Glycogen storage disease type IV (GSD IV), also called Andersen disease, or amylopectinosis, is a highly heterogeneous autosomal recessive disorder caused by a glycogen branching enzyme (GBE, 1,4-alpha-glucan branching enzyme) deficiency secondary to pathogenic variants on GBE1 gene. The incidence is evaluated to 1:600 000 to 1:800 000 of live births. GBE deficiency leads to an excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues (liver, skeletal muscle, heart, nervous system, etc.). Diagnosis is often guided by histological findings and confirmed by GBE activity deficiency and molecular studies. Severe neuromuscular forms of GSD IV are very rare and of disastrous prognosis. Identification and characterization of these forms are important for genetic counseling for further pregnancies. Here we describe clinical, histological, enzymatic, and molecular findings of 10 cases from 8 families, the largest case series reported so far, of severe neuromuscular forms of GSD IV along with a literature review. Main antenatal features are: fetal akinesia deformation sequence or arthrogryposis/joint contractures often associated with muscle atrophy, decreased fetal movement, cystic hygroma, and/or hydrops fetalis. If pregnancy is carried to term, the main clinical features observed at birth are severe hypotonia and/or muscle atrophy, with the need for mechanical ventilation, cardiomyopathy, retrognathism, and arthrogryposis. All our patients were stillborn or died within 1 month of life. In addition, we identified five novel GBE1 variants.

Keywords:  amylopectinosis; autopsy; glycogen branching enzyme 1; glycogenosis type IV; histology; polyglucosan; prenatal diagnosis; severe neuromuscular form

DOI:  https://doi.org/10.1002/jimd.12692
J Sport Health Sci. 2023 Nov 27. pii: S2095-2546(23)00115-1. [Epub ahead of print]

Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability: Insights from McArdle disease.

Pedro L Valenzuela, Alfredo Santalla, Lidia B Alejo, Andrea Merlo, Asunción Bustos, Laura Castellote-Bellés, Roser Ferrer-Costa, Nicola A Maffiuletti, David Barranco-Gil, Tomás Pinós, Alejandro Lucia.

   BACKGROUND: This study aimed to determine the effect of different carbohydrate (CHO) doses on exercise capacity in patients with McArdle disease-the paradigm of "exercise intolerance", characterized by complete muscle glycogen unavailability-and to determine whether higher exogenous glucose levels affect metabolic responses at the McArdle muscle cell (in vitro) level.
METHODS: Patients with McArdle disease (n = 8) and healthy controls (n = 9) underwent a 12-min submaximal cycling constant-load bout followed by a maximal ramp test 15 min after ingesting a non-caloric placebo. In a randomized, double-blinded, cross-over design, patients repeated the tests after consuming either 75 g or 150 g of CHO (glucose:fructose, 2:1). Cardiorespiratory, biochemical, perceptual, and electromyographic (EMG) variables were assessed. Additionally, glucose uptake and lactate appearance were studied in vitro in wild-type and McArdle mouse myotubes cultured with increasing glucose concentrations (0.35, 1.00, 4.50, and 10.00 g/L).
RESULTS: Compared with controls, patients showed the "classical" second-wind phenomenon (after prior disproportionate tachycardia, myalgia, and excess EMG activity during submaximal exercise, all p < 0.05) and an impaired endurance exercise capacity (-51% ventilatory threshold (VT) and -55% peak power output (PPO), both p < 0.001). Regardless of the CHO dose (p < 0.05 for both doses compared with the placebo), CHO intake increased blood glucose and lactate levels, decreased fat oxidation rates, and attenuated the second wind in the patients. However, only the higher dose increased VT (+27%, p = 0.010) and PPO (+18%, p = 0.007). In vitro analyses revealed no differences in lactate levels across glucose concentrations in wild-type myotubes, whereas a dose-response effect was observed in McArdle myotubes.
CONCLUSION: CHO intake exerts beneficial effects on exercise capacity in McArdle disease, a condition associated with total muscle glycogen unavailability. Some of these benefits were dose-dependent.

Keywords:  Endurance; Glycogen storage disease; Glycogenosis; Nutrition; Supplement

DOI:  https://doi.org/10.1016/j.jshs.2023.11.006
JPGN Rep. 2023 Nov;4(4): e377

Liver Biopsy Leads to Serendipitous Diagnosis of Glycogen Storage Disease Type IX in a Patient With Fontan-Associated Liver Disease.

Erin Hyer, Caitlin Alexander, Elizabeth B Rand, Tamir Diamond.

  Fontan-associated liver disease (FALD) is a form of congestive hepatopathy resulting from Fontan palliation procedures in patients with single ventricle physiology. Although there is variation between pediatric centers, the surveillance for FALD may include liver biopsies for assessment of degree of fibrosis. Our report describes a 7-year-old girl with hypoplastic left heart syndrome who underwent Fontan palliation at age 2, and presented with disproportionate hepatomegaly, elevated liver enzymes, and increased stiffness on liver elastography. Liver biopsy showed diffuse hepatocellular cytoplasmic glycogenation, leading to the diagnosis of glycogen storage disease IX. This case demonstrates the importance of investigating unexpected physical exam findings and the potential for serendipitous benefit of liver biopsy in FALD.

Keywords:  Fontan-associated liver disease; glycogen storage disease type IX; hypoglycemia; hypoplastic left heart syndrome

DOI:  https://doi.org/10.1097/PG9.0000000000000377
Adv Pharm Bull. 2023 Nov;13(4): 688-700

Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer's Disease.

Suggala Ramya Shri, Suman Manandhar, Yogendra Nayak, K Sreedhara Ranganath Pai.

  Glycogen synthase kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wide variety of biological processes, including early embryo formation, oncogenesis, as well cell death in neurodegenerative diseases. Several critical cellular processes in the brain are regulated by the GSK-3β, serving as a central switch in the signaling pathways. Dysregulation of GSK-3β kinase has been reported in diabetes, cancer, Alzheimer's disease, schizophrenia, bipolar disorder, inflammation, and Huntington's disease. Thus, GSK-3β is widely regarded as a promising target for therapeutic use. The current review article focuses mainly on Alzheimer's disease, an age-related neurodegenerative brain disorder. GSK-3β activation increases amyloid-beta (Aβ) and the development of neurofibrillary tangles that are involved in the disruption of material transport between axons and dendrites. The drug-binding cavities of GSK-3β are explored, and different existing classes of GSK-3β inhibitors are explained in this review. Non-ATP competitive inhibitors, such as allosteric inhibitors, can reduce the side effects compared to ATP-competitive inhibitors. Whereas ATP-competitive inhibitors produce disarrangement of the cytoskeleton, neurofibrillary tangles formation, and lead to the death of neurons, etc. This could be because they are binding to a site separate from ATP. Owing to their interaction in particular and special binding sites, allosteric ligands interact with substrates more selectively, which will be beneficial in resolving drug-induced resistance and also helpful in reducing side effects. Hence, in this review, we focussed on the allosteric GSK-3β inhibitors and discussed their futuristic opportunities as anti-Alzheimer's compounds.

Keywords:  ATP-competitive inhibitors; Allosteric inhibitors; Alzheimer’s disease; GSK-3β drug binding pockets; Glycogen synthase kinase-3beta; Proinflammatory cytokines

DOI:  https://doi.org/10.34172/apb.2023.071
PLoS One. 2023 ;18(11): e0288965

Mutational analysis and clinical investigations of medically diagnosed GSD 1a patients from Pakistan.

Bushra Gul, Sabika Firasat, Tayyaba Shan, Raeesa Tehreem, Kiran Afshan.

Glycogen storage disease type I (GSD I) is a rare autosomal recessive inborn error of carbohydrate metabolism caused by the defects of glucose-6-phosphatase complex (G6PC). Disease causing variants in the G6PC gene, located on chromosome 17q21 result in glycogen storage disease type Ia (GSD Ia). Age of onset of GSD Ia ranges from 0.5 to 25 years with presenting features including hemorrhage, hepatic, physical and blood related abnormalities. The overall goal of proposed study was clinical and genetic characterization of GSD Ia cases from Pakistani population. This study included forty GSD Ia cases presenting with heterogeneous clinical profile including hypoglycemia, hepatomegaly, lactic acidosis i.e., pH less than 7.2, hyperuricemia, seizures, epistaxis, hypertriglyceridemia (more than180 mg/dl) and sometimes short stature. All coding exons and intron-exon boundaries of G6PC gene were screened to identify pathogenic variant in 20 patients based on availability of DNA samples and willingness to participate in molecular analysis. Pathogenic variant analysis was done using PCR-Sanger sequencing method and pathogenic effect predictions for identified variants were carried out using PROVEAN, MutationTaster, Polyphen 2, HOPE, Varsome, CADD, DANN, SIFT and HSF software. Overall, 21 variants were detected including 8 novel disease causing variants i.e., G6PC (NM_000151.4):c.71A>C (p.Gln24Pro), c.109G>C(p.Ala37Pro), c.133G>C(p.Val45Leu), c.49_50insT c.205G>A(p.Asp69Asn), c.244C>A(p.Gln82Lys) c.322A>C(p.Thr108Pro) and c.322A>C(p.Cys284Tyr) in the screened regions of G6PC gene. Out of 13 identified polymorphisms, 3 were identified in heterozygous condition while 10 were found in homozygous condition. This study revealed clinical presentation of GSD Ia cases from Pakistan and identification of novel disease-causing sequence variants in coding region and intron-exon boundaries of G6PC gene.

DOI: https://doi.org/10.1371/journal.pone.0288965
Front Neurol. 2023 ;14 1261125

Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder.

Joseph R Abraham, Frederick M Allen, John Barnard, Daniela Schlatzer, Marvin R Natowicz.

  Inadequate glycogen branching enzyme 1 (GBE1) activity results in different forms of glycogen storage disease type IV, including adult polyglucosan body disorder (APBD). APBD is clinically characterized by adult-onset development of progressive spasticity, neuropathy, and neurogenic bladder and is histologically characterized by the accumulation of structurally abnormal glycogen (polyglucosan bodies) in multiple cell types. How insufficient GBE1 activity causes the disease phenotype of APBD is poorly understood. We hypothesized that proteomic analysis of tissue from GBE1-deficient individuals would provide insights into GBE1-mediated pathobiology. In this discovery study, we utilized label-free LC-MS/MS to quantify the proteomes of lymphoblasts from 3 persons with APBD and 15 age- and gender-matched controls, with validation of the findings by targeted MS. There were 531 differentially expressed proteins out of 3,427 detected between APBD subjects vs. controls, including pronounced deficiency of GBE1. Bioinformatic analyses indicated multiple canonical pathways and protein-protein interaction networks to be statistically markedly enriched in APBD subjects, including: RNA processing/transport/translation, cell cycle control/replication, mTOR signaling, protein ubiquitination, unfolded protein and endoplasmic reticulum stress responses, glycolysis and cell death/apoptosis. Dysregulation of these processes, therefore, are primary or secondary factors in APBD pathobiology in this model system. Our findings further suggest that proteomic analysis of GBE1 mutant lymphoblasts can be leveraged as part of the screening for pharmaceutical agents for the treatment of APBD.

Keywords:  GBE1; adult polyglucosan body disease; glycogen branching enzyme; glycogen storage disease; lymphoblast; neurodegeneration; pathogenesis; proteomic

DOI:  https://doi.org/10.3389/fneur.2023.1261125
Heliyon. 2023 Nov;9(11): e22008

Glucoregulatory effect of butyrate is associated with elevated circulating VEGF and reduced cardiac lactate in high fructose fed rats.

Adewumi Oluwafemi Oyabambi, Olubayode Bamidele, Aindero Blessing Boluwatife, Lawrence Dayo Adedayo.

   Background: High fructose diet has been linked with impaired body metabolism and cardiovascular diseases. Sodium butyrate (NaB) was documented to improve glucoregulation and cardiometabolic problems associated with high fructose diet (HFrD) but the mechanisms behind it are unclear. As a result, the purpose of this study was to look into the effects of NaB on VEGF and cardiac lactate in HFrD-induced dysmetabolism.
Methods: Twenty male Wistar rats of weight 130-140 g were assigned randomly after a week of acclimation into four groups: Control diet (CTR), High fructose drink (HFrD); 10 % (w/v), NaB (200 mg/kg bw), and HFrD + NaB (200 mg/kg bw). The animals were induced to be unconscious with 50 mg/kg of pentobarbital sodium intraperitoneally, blood samples were taken via cardiac puncture and cardiac tissue homogenates were obtained for Fasting Blood Sugar (FBS) and plasma insulin, cardiac glycogen, plasma and cardiac glycogen synthase, plasma and cardiac nitric oxide as well as vascular endothelial growth factor (VEGF).
Result: HFrD resulted in statistical elevation body and cardiac weight, plasma glucose, plasma insulin, cardiac lactate, glycogen and decreased nitric oxide level (NO) when compared with the control group. Administration of NaB reduced cardiac weight, blood glucose, plasma insulin, cardiac lactate while nitric oxide and glycogen increased (P < 0.05). NaB increased plasma glycogen synthase in normal rats, plasma and cardiac circulating VEGF in HFrD administered rats (P < 0.05) while no change was produced in plasma and cardiac glycogen synthase level of HFrD treated rats.
Conclusion: Sodium butyrate improves glucoregulation by reducing cardiac lactate and increasing circulating VEGF in HFrD-treated rats.

Keywords:  Cardiometabolic disorders; Gh fructose drink; Glucoregulation; HiSodium butyrate; High fructose drink; Sodium butyrate; Vascular endothelial growth factor

DOI:  https://doi.org/10.1016/j.heliyon.2023.e22008
Brain Circ. 2023 Jul-Sep;9(3):9(3): 162-171

Glycogen synthase kinase-3β mediates toll-like receptors 4/nuclear factor kappa-B-activated cerebral ischemia-reperfusion injury through regulation of fat mass and obesity-associated protein.

Kaiwei Xu, Wenwen Du, Xiuxiu Zhuang, Dongdong Liang, Yunchang Mo, Junlu Wang.

   BACKGROUND: Glycogen synthase kinase-3β (GSK3β), fat mass and obesity-associated protein (FTO), and toll-like receptors 4 (TLR4) take on critical significance in different biological processes, whereas their interactions remain unclear. The objective was the investigation of the interaction effect in cerebral ischemia-reperfusion (I/R) injury.
METHODS: The function of the cerebral cortex in the mouse middle cerebral artery occlusion (MCAO) model (each group n = 6) and P12 cells oxygen-glucose deprivation/reoxygenation (OGD/R) model was analyzed using short hairpin GSK3β lentivirus and overexpression of FTO lentivirus (in vitro), TLR4 inhibitor (TAK242), and LiCl to regulate GSK3β, FTO, TLR4 expression, and GSK3β activity, respectively.
RESULTS: After GSK3β knockdown in the OGD/R model of PC12 cells, the levels of TLR4 and p-p65 were lower than in the control, and the level of FTO was higher than in the control. Knockdown GSK3β reversed the OGD/R-induced nuclear factor kappa-B transfer to the intranuclear nuclei. As indicated by the result, TLR4 expression was down-regulated by overexpressed FTO, and TLR4 expression was up-regulated notably after inhibition of FTO with the use of R-2HG. After the inhibition of the activity of GSK3β in vivo, the reduction of FTO in mice suffering from MCAO was reversed.
CONCLUSIONS: Our research shows that GSK3β/FTO/TLR4 pathway contributes to cerebral I/R injury.

Keywords:  Cerebral ischemia-reperfusion injury; N6-methyladenosine; fat mass and obesity-associated protein; glucose-oxygen deprivation/reoxygenation; glycogen synthase kinase-3β; middle cerebral artery occlusion; nuclear factor kappa-B; stroke; toll-like receptors 4

DOI:  https://doi.org/10.4103/bc.bc_3_23
Am J Physiol Endocrinol Metab. 2023 Nov 29.

Skeletal muscle-specific inducible AMPKα1/α2 knockout mice develop muscle weakness, glycogen depletion, and fibrosis that persists during disuse atrophy.

Jonathan J Petrocelli, Jingtong Liu, Elena M Yee, Patrick J Ferrara, Paul-Emile Bourrant, Naomi M M P de Hart, Sean M Tatum, William J Holland, Katsuhiko Funai, Micah J Drummond.

  The 5' adenosine monophosphate-activated protein kinase (AMPK) is an important skeletal muscle regulator implicated as a possible therapeutic target to ameliorate the local undesired deconditioning of disuse atrophy. However, the muscle-specific role of AMPK in regulating muscle function, fibrosis, and transcriptional reprogramming during physical disuse are unknown. The purpose of this study was to determine how the absence of both catalytic subunits of AMPK in skeletal muscle influence muscle force production, collagen deposition, and the transcriptional landscape. We generated skeletal muscle-specific tamoxifen inducible AMPKα1/α2 knock out (AMPKα-/-) mice that underwent 14 days of hindlimb unloading (HU) or remained ambulatory for 14 days (AMB). We found that AMPKα-/- during ambulatory conditions altered body weight and myofiber size, decreased muscle function, depleted glycogen stores and TBC1 domain family member 1 (TBC1D1) phosphorylation, increased collagen deposition, and altered transcriptional pathways. Primarily pathways related to cellular senescence, and mitochondrial biogenesis and function were influenced by the absence of AMPKα. The effects of AMPKα-/- persisted, but were not worsened, following hindlimb unloading. Together, we report that AMPKα is necessary to maintain skeletal muscle quality.

Keywords:  AMPK; collagen; hindlimb unloading; muscle fatigue; senescence

DOI:  https://doi.org/10.1152/ajpendo.00261.2023
J Cachexia Sarcopenia Muscle. 2023 Dec 02.

Lack of vitamin D signalling shifts skeletal muscles towards oxidative metabolism.

Anamica Das, Neha Jawla, Vaidehee Meena, Suchitra D Gopinath, Gopalakrishnan Aneeshkumar Arimbasseri.

   BACKGROUND: Mice lacking vitamin D receptor (VDR) exhibit a glycogen storage disorder, disrupting carbohydrate utilization in muscle. Here, we asked if the defective carbohydrate metabolism alters the fat utilization by the skeletal muscles of vdr-/- mice.
METHODS: To check the effect of high-fat-containing diets on muscle mass and metabolism of vdr-/- mice, we subjected them to two different milk fat-based diets (milk fat diet with 60% of energy from milk fat and milk-based diet [MBD] with 37% of energy from milk fat) and lard-based high-fat diet (HFD) containing 60% of energy from lard fat. Skeletal muscles and pancreas from these mice were analysed using RNA sequencing, quantitative reverse transcription polymerase chain reaction and western blot to understand the changes in signalling and metabolic pathways. Microscopic analyses of cryosections stained with haematoxylin and eosin, BODIPY, succinate dehydrogenase and periodic acid-Schiff reagent were performed to understand changes in morphology and metabolism of muscle fibres and pancreatic islets.
RESULTS: Transcriptomic analyses showed that the skeletal muscles of vdr-/- mice exhibit upregulation of the fatty acid oxidation pathways, suggesting a shift towards increased lipid utilization even in a carbohydrate-enriched regular chow diet (chow). Two different milk fat-enriched diets restored body weight (12.01 ± 0.33 g in chow vs. 17.99 ± 0.62 g in MBD) and muscle weights (38.58 ± 3.84 mg in chow vs. 110.72 ± 1.96 mg in MBD for gastrocnemius [GAS]) of vdr-/- mice. Muscle ATP levels (0.56 ± 0.18 μmol in chow vs. 1.48 ± 0.08 μmol in MBD) and protein synthesis (0.25 ± 0.04 A.U. in chow vs. 2.02 ± 0.06 A.U. in MBD) were upregulated by MBD. However, despite increasing muscle energy levels, HFD failed to restore the muscle mass and cross-sectional area to that of wild-type (WT) mice (104.95 ± 2.6 mg for WT mice on chow vs. 77.26 ± 1.7 mg for vdr-/- mice on HFD for GAS). Moreover, HFD disrupted glucose homeostasis in vdr-/- mice, while MBD restored it. We further analysed insulin response and pancreatic insulin levels of these mice to show that HFD led to reduced insulin levels in pancreatic beta cells of vdr-/- mice (mean intensity of 1.5 × 10-8 for WT mice on chow vs. 4.3 × 10-9 for vdr-/- mice on HFD). At the same time, MBD restored glucose-stimulated pancreatic insulin response (mean intensity of 9.2 × 10-9 ).
CONCLUSIONS: Skeletal muscles of vdr-/- mice are predisposed to utilize fatty acids as their primary energy source to circumvent their defective carbohydrate utilization. Thus, HFDs could restore energy levels in the skeletal muscles of vdr-/- mice. This study reveals that when mice are subjected to a lard-based HFD, VDR signalling is essential for maintaining insulin levels in pancreatic islets. Our data show a critical role of VDR in muscle metabolic flexibility and pancreatic insulin response.

Keywords:  VDR; energy metabolism; glucose homeostasis; insulin; milk fat diet; skeletal muscle; vitamin D

DOI:  https://doi.org/10.1002/jcsm.13378