scholarly journals Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hui J. Wang ◽  
Chang Seok Lee ◽  
Rachel Sue Zhen Yee ◽  
Linda Groom ◽  
Inbar Friedman ◽  
...  
Keyword(s):  
Muscle Metabolism ◽  
Malignant Hyperthermia Susceptibility ◽  
Lifestyle Modifications ◽  
Release Channel ◽  
Adaptive Thermogenesis ◽  
Pathogenic Variants ◽  
Brown Adipose ◽  
Heat Response ◽  
Life Threatening ◽  
Lactate Levels

Abstract Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.

Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia

2017 ◽  
Vol 49 (2) ◽  
pp. 81-87 ◽  
Author(s):  
Teresa A. Beam ◽  
Emily F. Loudermilk ◽  
David F. Kisor
Keyword(s):  
Malignant Hyperthermia ◽  
Malignant Hyperthermia Susceptibility ◽  
Incomplete Penetrance ◽  
Variable Expression ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Gated Channel ◽  
Life Threatening ◽  
Ryanodine Receptor 1 ◽  
Significant Linkage

A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S ( CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.

scholarly journals Inactivation of the adrenergic receptor β2 disrupts glucose homeostasis in mice

2014 ◽  
Vol 221 (3) ◽  
pp. 381-390 ◽  
Author(s):  
Gustavo W Fernandes ◽  
Cintia B Ueta ◽  
Tatiane L Fonseca ◽  
Cecilia H A Gouveia ◽  
Carmen L Lancellotti ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Expenditure ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Liver Steatosis ◽  
Mrna Levels ◽  
High Fat ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
Similar Body

Three types of beta adrenergic receptors (ARβ1–3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse withArβ2knockout (ARβ2KO). At room temperature, ARβ2KO mice have normal core temperature and, upon acute cold exposure (4 °C for 4 h), ARβ2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARβ2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and ofArβ1, andArβ3mRNA levels. In addition, ARβ2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepaticPepck(Pck1) mRNA levels. The animals were fed a high-fat diet (40% fat) for 6 weeks, ARβ2KO mice doubled their caloric intake, accelerated energy expenditure, and inducedUcp1expression in a manner similar to WT controls, exhibiting a similar body weight gain and increase in the size of white adipocytes to the WT controls. However, ARβ2KO mice maintain fasting hyperglycemia as compared with WT controls despite very elevated insulin levels, but similar degrees of liver steatosis and hyperlipidemia. In conclusion, inactivation of the ARβ2KO pathway preserves cold- and diet-induced adaptive thermogenesis but disrupts glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion. Feeding on a high-fat diet worsens the metabolic imbalance, with significant fasting hyperglycemia but similar liver structure and lipid profile to the WT controls.

scholarly journals Acute Onset Peripartum Cardiomyopathy in a Woman with Severe Pre-eclamptia: A Diagnostic Dilemma

2013 ◽  
Vol 6 (1) ◽  
pp. 33-34 ◽  
Author(s):  
Sonela Basak ◽  
Pallab Rudra
Keyword(s):  
Late Pregnancy ◽  
Acute Onset ◽  
Peripartum Cardiomyopathy ◽  
Lifestyle Modifications ◽  
Diagnostic Dilemma ◽  
Life Threatening ◽  
Physiological Reserve ◽  
Proper Diagnosis ◽  
Future Pregnancy ◽  
Lateral Thinking

Peripartum cardiomyopathy (PPCM) is a form of dilated cardiomyopathy that can present as acute life-threatening pulmonary oedema in late pregnancy or early puerperium, its diagnosis is mainly by exclusion of other causes. Morbidity is high due to the reduced physiological reserve in pregnancy. PPCM and severe pre-eclampsia can co-exist and their clinical presentation may overlap, making the diagnosis more difficult and often delayed, with potentially devastating consequences. Here, we would like to share our experience of such a case and present to the readers how we dealt with the challenge. As obstetricians we often do not resort to transthoracic echocardiography, which in our case prompted the diagnosis timely. Lateral thinking and a heightened suspicion does help. Proper diagnosis is extremely important not only for the immediate appropriate management but also for advising long-term lifestyle modifications to minimize risk and counselling for future pregnancy.

scholarly journals GPR120 controls neonatal brown adipose tissue thermogenic induction

2019 ◽  
Vol 317 (5) ◽  
pp. E742-E750 ◽  
Author(s):  
Tania Quesada-López ◽  
Aleix Gavaldà-Navarro ◽  
Samantha Morón-Ros ◽  
Laura Campderrós ◽  
Roser Iglesias ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Uncoupling Protein ◽  
Receptor Protein ◽  
Brown Adipocyte ◽  
Fibroblast Growth Factor 21 ◽  
Acid Oxidation ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
G Protein Coupled

Adaptive induction of thermogenesis in brown adipose tissue (BAT) is essential for the survival of mammals after birth. We show here that G protein-coupled receptor protein 120 (GPR120) expression is dramatically induced after birth in mouse BAT. GPR120 expression in neonatal BAT is the highest among GPR120-expressing tissues in the mouse at any developmental stage tested. The induction of GPR120 in neonatal BAT is caused by postnatal thermal stress rather than by the initiation of suckling. GPR120-null neonates were found to be relatively intolerant to cold: close to one-third did not survive at 21°C, but all such pups survived at 25°C. Heat production in BAT was significantly impaired in GPR120-null pups. Deficiency in GPR120 did not modify brown adipocyte morphology or the anatomical architecture of BAT, as assessed by electron microscopy, but instead impaired the expression of uncoupling protein-1 and the fatty acid oxidation capacity of neonatal BAT. Moreover, GPR120 deficiency impaired fibroblast growth factor 21 (FGF21) gene expression in BAT and reduced plasma FGF21 levels. These results indicate that GPR120 is essential for neonatal adaptive thermogenesis.

scholarly journals The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin

2017 ◽  
Vol 32 (4) ◽  
pp. 345-358 ◽  
Author(s):  
Emma Henriksson ◽  
Anne-Laure Huber ◽  
Erin K. Soto ◽  
Anna Kriebs ◽  
Megan E. Vaughan ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Time Of Day ◽  
Glucose Response ◽  
Biological Responses ◽  
Circadian Time ◽  
Lower Blood ◽  
Life Threatening ◽  
Lactate Levels ◽  
Amp Activated Protein Kinase ◽  
Glucose Reduction

Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP-activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms affect the biological responses to metformin in a complex manner.

scholarly journals Experimental approach to overexpress pituitary adenylate cyclase activating polypeptide (PACAP) specifically in the hypothalamus

2021 ◽  
Author(s):  
◽  
Yamna Rahim
Keyword(s):  
Energy Expenditure ◽  
Experimental Approach ◽  
Health Condition ◽  
Specific Expression ◽  
Steroidogenic Factor 1 ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
Pituitary Adenylate Cyclase ◽  
The Brain

Obesity is adetrimental health condition that occurs when energy intake, exceeds energy expenditure. Pituitary adenylatecyclase-activating polypeptide (PACAP) regulates energy expenditure, including adaptive thermogenesis, through the hypothalamic-sympatheticnervous system-brown adipose tissue axis. We hypothesize that PACAP expression in the ventromedial nucleus (VMN) is required for adaptive thermogenesis. To assess this, our goal is to develop an animal model that expresses PACAP specifically in the VMN of the hypothalamus. As a first step to achieving this goal, we established a protocol to deliver an adeno-associatedvirus (AAV) expressing the visible protein eGFP under the control of a VMN-specific promoter, steroidogenic factor 1 (SF1) using stereotaxic surgery. A second step was to develop a protocol to detect PACAP mRNA in the brain using in situ hybridization. Our results showed that the stereotaxic protocol was successful and provides significant progress towards achieving PACAP-specific expression in the VMN.

scholarly journals Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Meng Yuan ◽  
Yi Guo ◽  
Hong Xia ◽  
Hongbo Xu ◽  
Hao Deng ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Patients ◽  
Splicing Variant ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Gated Channel ◽  
Life Threatening ◽  
Glycerol 3 Phosphate Dehydrogenase

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A>C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A>T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

scholarly journals SIGNIFICANCE OF LACTATE ESTIMATION IN DEBILITATED MYOPATHIES AND TREATMENT PROGRAMS Lactate levels in myopathies

2013 ◽  
Vol 2 (1) ◽  
pp. 3-5
Author(s):  
Junaid Mahmood Alam ◽  
Sumaira Imran Farooqui ◽  
Amna Hussain ◽  
Syed Riaz Mahmood ◽  
Suad Naheed ◽  
...  
Keyword(s):  
Physical Therapy ◽  
Aerobic Capacity ◽  
Aerobic Training ◽  
Lactate Concentration ◽  
Muscle Metabolism ◽  
Treatment Programs ◽  
Gradual Decline ◽  
Muscle Strengthening ◽  
Strengthening Exercises ◽  
Lactate Levels

BACKGROUND Metabolic alteration such as acidosis and abnormally high levels of lactate productions are responsible for development of disabilities in polymyositis and dermatomyositis. Interestingly, this has been suggested that by proper aerobic training, combined with muscle strengthening exercises, shows improve aerobic capacity and muscle metabolism. AIM AND OBJECTIVES The present study was undertaken to evaluate lactate concentrations in myopathy patients and determines the efficacy of exercise therapy in improving aerobic status of such patients. MATERIALS AND METHODS Selected myopathy patients grouped as PM (n = 12 patients) and DM (n = 8 patients). The effects of physical therapy treatments were assessed by lactate estimation at zero, 15th and 28th days. RESULTS Gradual decline in lactate concentration was noted in both PM and DM group, however more prominently in later than in former. The total decline in lactate levels from zero days to 28th day was 42% for PM patients and a considerable 63% for DM patients. CONCLUSION It was suggested that estimation of lactate levels in PM and DM patients is of some metabolic importance and physiotherapy treatments did cause improvement in aerobic efficiency of muscles, which was depicted by periodic decline in lactate concentration after 15 and 28 days.

scholarly journals Genetic basis and molecular biology of cardiac arrhythmias in cardiomyopathies

2020 ◽  
Vol 116 (9) ◽  
pp. 1600-1619 ◽  
Author(s):  
Ali J Marian ◽  
Babken Asatryan ◽  
Xander H T Wehrens
Keyword(s):  
Molecular Biology ◽  
Cardiac Arrhythmias ◽  
Genetic Basis ◽  
Structural Changes ◽  
Causal Role ◽  
Ion Currents ◽  
Pathogenic Variants ◽  
Life Threatening ◽  
Shared Genetic

Abstract Cardiac arrhythmias are common, often the first, and sometimes the life-threatening manifestations of hereditary cardiomyopathies. Pathogenic variants in several genes known to cause hereditary cardiac arrhythmias have also been identified in the sporadic cases and small families with cardiomyopathies. These findings suggest a shared genetic aetiology of a subset of hereditary cardiomyopathies and cardiac arrhythmias. The concept of a shared genetic aetiology is in accord with the complex and exquisite interplays that exist between the ion currents and cardiac mechanical function. However, neither the causal role of cardiac arrhythmias genes in cardiomyopathies is well established nor the causal role of cardiomyopathy genes in arrhythmias. On the contrary, secondary changes in ion currents, such as post-translational modifications, are common and contributors to the pathogenesis of arrhythmias in cardiomyopathies through altering biophysical and functional properties of the ion channels. Moreover, structural changes, such as cardiac hypertrophy, dilatation, and fibrosis provide a pro-arrhythmic substrate in hereditary cardiomyopathies. Genetic basis and molecular biology of cardiac arrhythmias in hereditary cardiomyopathies are discussed.

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