bims-kimdis 2024-05-12 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒05‒12
thirteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Acetoacetate and D- and L-β-hydroxybutyrate have distinct effects on basal and insulin-stimulated glucose uptake in L6 skeletal muscle cells.
Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use.
The Significant Impact of High-Fat, Low-Carbohydrate Ketogenic Diet on Serum Lipid Profile and Atherosclerotic Cardiovascular Disease Risk in Overweight and Obese Adults.
Ketogenic diet time-dependently prevents NAFLD through upregulating the expression of antioxidant protein metallothionein-2.
Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review.
Drug-resistant epilepsy and ketogenic diet therapy - a qualitative study of families' experiences.
High-intensity interval training impacts skeletal muscle core clock in overweight and obese men with insulin resistance.
Exercise ameliorates muscular excessive mitochondrial fission, insulin resistance and inflammation in diabetic rats via irisin/AMPK activation.
Nutritional Strategies for Muscle Atrophy: Current Evidence and Underlying Mechanisms.
Beneficial Effects of High-Intensity Interval Training and Dietary Changes Intervention on Hepatic Fat Accumulation in HFD-Induced Obese Rats.
Unlocking Pathways That Improve Cardiac Function in Chronic Heart Failure: Are Ketones the Key?
Effects of post-exercise intake of exogenous lactate on energy substrate utilization at rest.
The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.

Am J Physiol Cell Physiol. 2024 May 06.

Acetoacetate and D- and L-β-hydroxybutyrate have distinct effects on basal and insulin-stimulated glucose uptake in L6 skeletal muscle cells.

Hannah Khouri, Mathilde Roberge, John R Ussher, Céline Aguer.

  Ketone bodies (acetoacetate and β-hydroxybutyrate) are oxidized in skeletal muscle mainly during fasting as an alternative source of energy to glucose. Prior studies suggest that there is a negative relationship between increased muscle ketolysis and muscle glucose metabolism in mice with obesity and/or type 2 diabetes. Therefore, we investigated the connection between increased ketone body exposure and muscle glucose metabolism by measuring the effect of a 3-hour exposure to ketone bodies on glucose uptake in differentiated L6 myotubes. We showed that exposure to acetoacetate at a typical concentration (0.2 mM) resulted in increased basal glucose uptake in L6 myotubes, which was dependent on increased membrane GLUT4 translocation. Basal and insulin-stimulated glucose uptake was also increased with a concentration of acetoacetate reflective of diabetic ketoacidosis or a ketogenic diet (1 mM). We found that β-hydroxybutyrate had a variable effect on basal glucose uptake, in that a racemic mixture of the two β-hydroxybutyrate enantiomers (D and L) appeared to decrease basal glucose uptake, while 3 mM D-β-hydroxybutyrate alone increased basal glucose uptake. However, the effects of the ketone bodies individually were not observed when acetoacetate was present in combination with β-hydroxybutyrate. These results provide insight that will help elucidate the effect of ketone bodies in the context of specific metabolic diseases and nutritional states (e.g., type 2 diabetes and ketogenic diets).

Keywords:  acetoacetate; glucose uptake; ketone bodies; skeletal muscle; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00718.2023
Cells. 2024 May 04. pii: 784. [Epub ahead of print]13(9):

Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use.

Filippo Annoni, Elisa Gouvea Bogossian, Lorenzo Peluso, Fuhong Su, Anthony Moreau, Leda Nobile, Stefano Giuseppe Casu, Elda Diletta Sterchele, Lorenzo Calabro, Michele Salvagno, Mauro Oddo, Fabio Silvio Taccone.

  Cardiac arrest survivors suffer the repercussions of anoxic brain injury, a critical factor influencing long-term prognosis. This injury is characterised by profound and enduring metabolic impairment. Ketone bodies, an alternative energetic resource in physiological states such as exercise, fasting, and extended starvation, are avidly taken up and used by the brain. Both the ketogenic diet and exogenous ketone supplementation have been associated with neuroprotective effects across a spectrum of conditions. These include refractory epilepsy, neurodegenerative disorders, cognitive impairment, focal cerebral ischemia, and traumatic brain injuries. Beyond this, ketone bodies possess a plethora of attributes that appear to be particularly favourable after cardiac arrest. These encompass anti-inflammatory effects, the attenuation of oxidative stress, the improvement of mitochondrial function, a glucose-sparing effect, and the enhancement of cardiac function. The aim of this manuscript is to appraise pertinent scientific literature on the topic through a narrative review. We aim to encapsulate the existing evidence and underscore the potential therapeutic value of ketone bodies in the context of cardiac arrest to provide a rationale for their use in forthcoming translational research efforts.

Keywords:  anoxic brain injury; cerebral metabolism; heart arrest; ischemia–reperfusion; ketone bodies

DOI:  https://doi.org/10.3390/cells13090784
Cureus. 2024 Apr;16(4): e57920

The Significant Impact of High-Fat, Low-Carbohydrate Ketogenic Diet on Serum Lipid Profile and Atherosclerotic Cardiovascular Disease Risk in Overweight and Obese Adults.

Shadan Khdher, Salm Mohammed, Kwestan Muhammed, Abdulrahman Ismael.

  Background and objectives Overweight and obesity are becoming more commonplace globally. The ketogenic diet (KD), also known as the high-fat, low-carbohydrate diet, has become increasingly popular in recent years as a means to lose weight quickly. This present study aims to examine the clinical effects of ketogenic diets in individuals who are obese or overweight by evaluating or assessing variations in metabolic parameters associated with lipid control, the risk of atherosclerotic cardiovascular disease, and other kidney risk indicators. Methods and subjects This observational case-control research involved 250 individuals in total and was conducted from May 2023 to January 2024. Of these, 158 were on a ketogenic diet, and 92 adults not following any type of diet were chosen to serve as controls. The biochemistry parameters of the kidney function test and lipid profile were measured for the two comparing groups. Data were analyzed for statistical significance using the Student t-test, Mann-Whitney U test, and one-way analysis of variance (ANOVA), followed by a post hoc test (least significant difference (LSD)). Chi-square tests were employed in the analysis to compare proportions. Results Out of 250 participants, there was a 20-80 age range, with their median age being 40 years old. The two comparing groups' lipid profiles were very different from one another; the cardiovascular risk (triglyceride (TG)/high-density lipoprotein (HDL)), total cholesterol, low-density lipoprotein (LDL), and triglyceride levels were all greater in the KD group when compared to the non-KD group. The mean LDL cholesterol (LDL-C) of the normal-weight participants was 56 mg/dL (p=0.079). Thereafter, it experienced a significant rise to 97.58 mg/dL and 108.2 mg/dL in those individuals who were overweight and obese, respectively (p<0.020). Conclusions As obesity rates in the populace keep rising, dietary fads such as the ketogenic diet are gaining traction. Although they could help with weight loss, this study had a notable observation of severe hypercholesterolemia and increased risk of atherosclerotic cardiovascular disease among the ketogenic diet participants. Additional research is necessary to ascertain if a ketogenic diet can be sustained over the long term and how it affects endpoints that are more clinically significant, such as morbidity and mortality due to obesity.

Keywords:  body mass index; cardiovascular risk; ketogenic diet; lipid profile; obesity; overweight

DOI:  https://doi.org/10.7759/cureus.57920
Clin Nutr. 2024 Apr 22. pii: S0261-5614(24)00135-3. [Epub ahead of print]43(6): 1475-1487

Ketogenic diet time-dependently prevents NAFLD through upregulating the expression of antioxidant protein metallothionein-2.

Yuehua You, Yi Huang, Xiaoyang Wang, Hongbin Ni, Qin Ma, Haiying Ran, Jingshu Cai, Xiaojing Lin, Ting Luo, Chaodong Wu, Xiaoqiu Xiao, Li Ma.

  BACKGROUND & AIMS: The past few decades have witnessed a rapid growth in the prevalence of nonalcoholic fatty liver disease (NAFLD). While the ketogenic diet (KD) is considered for managing NAFLD, the safety and efficacy of the KD on NAFLD has been a controversial topic. Here, we aimed to investigate the effect of KD of different durations on metabolic endpoints in mice with NAFLD and explore the underlying mechanisms.METHODS: NAFLD mice were fed with KD for 1, 2, 4 and 6 weeks, respectively. The blood biochemical indexes (blood lipids, AST, ALT and etc.) and liver fat were measured. The LC-MS/MS based proteomic analysis was performed on liver tissues. Metallothionein-2 (MT2) was knocked down with adeno-associated virus (AAV) or small interfering RNA (siRNA) in NAFLD mice and AML-12 cells, respectively. H&E, BODIPY and ROS staining were performed to examine lipid deposition and oxidative stress. Furthermore, MT2 protein levels, nucleus/cytoplasm distribution and DNA binding activity of peroxisome proliferators-activated receptors α (PPARα) were evaluated.
RESULTS: KD feeding for 2 weeks showed the best improvement on NAFLD phenotype. Proteomic analysis revealed that MT2 was a key candidate for different metabolic endpoints of NAFLD affected by different durations of KD feeding. MT2 knockdown in NAFLD mice blocked the effects of 2 weeks of KD feeding on HFD-induced steatosis. In mouse primary hepatocytes and AML-12 cells, MT2 protein levels were induced by β-hydroxybutyric acid (β-OHB). MT2 Knockdown blunted the effects of β-OHB on alleviating PA-induced lipid deposition. Mechanistically, 2 weeks of KD or β-OHB treatment reduced oxidative stress and upregulated the protein levels of MT2 in nucleus, which subsequently increased its DNA binding activity and PPARα protein expression.
CONCLUSIONS: Collectively, these findings indicated that KD feeding prevented NAFLD in a time dependent manner and MT2 is a potential target contributing to KD improvement on steatosis.

Keywords:  Ketogenic diet; Lipid accumulation; MT2; NAFLD; PPARα

DOI:  https://doi.org/10.1016/j.clnu.2024.04.029
J Nutr Metab. 2024 ;2024 9672969

Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review.

Nike Meer, Tobias Fischer.

Pathomechanisms of dementias involve increasing damage to neuronal energy metabolism, resulting in degeneration-related insulin resistance and glucose hypometabolism. In this case, ketone bodies can provide an alternative energy source. Supplementation with medium-chain triglycerides (MCTs), which can induce ketogenesis, may alleviate brain energy deficits and improve neuronal function. This review aims to determine the effectiveness of MCT as a symptomatic treatment approach. The systematic literature search was conducted in April 2023 following the Cochrane Handbook and PRISMA guidelines. A total of 21 studies were included, comprising eight uncontrolled trials and 13 RCTs investigating the effects of MCT on Alzheimer's disease (AD) and mild cognitive impairment (MCI). A substantial increase in plasma ketone levels and brain metabolic rates was observed. Cognitive assessments showed only occasional or domain-specific performance improvements. The effects on functional abilities or psychological outcomes have been inadequately studied. Besides gastrointestinal side effects, no harmful effects were observed. However, the evidence was severely weakened by heterogeneous and poorly designed study protocols, bias, and conflicts of interest. In conclusion, the ketogenic properties of MCTs may have beneficial effects on brain metabolism in AD and MCI but do not always result in measurable clinical improvement. Current evidence is insufficient to recommend MCT as a comparable symptomatic treatment option.

DOI: https://doi.org/10.1155/2024/9672969
Seizure. 2024 Apr 26. pii: S1059-1311(24)00129-8. [Epub ahead of print]118 137-147

Drug-resistant epilepsy and ketogenic diet therapy - a qualitative study of families' experiences.

Jennifer H Carroll, Tracey Parkin, J Helen Cross, Mary Hickson, Emma Williams, Val Aldridge, Avril Collinson.

  BACKGROUND: A diagnosis of drug-resistant epilepsy is life changing for a family. Ketogenic diet therapy (KDT) can offer hope when other treatments have failed. However, it often requires a significant change in daily routine and dietary habits. This qualitative descriptive study aimed to explore families' experiences of epilepsy and KDT.METHODS: Parents of a child aged ≤18 years with epilepsy, currently or recently treated with KDT, were recruited from the UK and internationally via UK Ketogenic Diet (KD) centres, charities, and social media. Semi-structured interviews were audio recorded, transcribed verbatim, anonymised, coded using Nvivo (V12), and inductive thematic analysis undertaken.
RESULTS: Twenty-one parents participated. Four themes and 12 subthemes emerged: 1. 'Epilepsy is all consuming' explored the impact of epilepsy on the family. 2. 'KD provides a window to new opportunities' explores the motivators for KDT and positive outcomes. 3. 'The reality of KD' explores day to day life and how families adapt to KD. 4. 'Looking to the future' explores the factors that may make KD easier for families. All were glad their child trialled KD, even when less successful. The importance of a support network including family, friends, charity organisations and the KD team was evident across all themes.
CONCLUSIONS: We conclude with five recommendations to help support families in their management of KDT; Improved access to KDT and transition to adult services, access to quality education and support, enhanced variety of KD foods, regular social education and finally consideration of peer mentoring.

Keywords:  Epilepsy; Family; Interviews; Ketogenic diet; Outcomes; Parents; Quality of life

DOI:  https://doi.org/10.1016/j.seizure.2024.04.024
J Physiol. 2024 May 09.

High-intensity interval training impacts skeletal muscle core clock in overweight and obese men with insulin resistance.

Larissa Moreira Dias, Guilherme Correia Ferri Antonio.



Keywords:  chronic exercise; clock genes; metabolism; skeletal muscle

DOI:  https://doi.org/10.1113/JP286165
Sci Rep. 2024 05 09. 14(1): 10658

Exercise ameliorates muscular excessive mitochondrial fission, insulin resistance and inflammation in diabetic rats via irisin/AMPK activation.

Junjie Lin, Xin Zhang, Yu Sun, Haocheng Xu, Nan Li, Yuanxin Wang, Xin Tian, Chen Zhao, Bin Wang, Baishu Zhu, Renqing Zhao.

  This study aimed to investigate the effects of exercise on excessive mitochondrial fission, insulin resistance, and inflammation in the muscles of diabetic rats. The role of the irisin/AMPK pathway in regulating exercise effects was also determined. Thirty-two 8-week-old male Wistar rats were randomly divided into four groups (n = 8 per group): one control group (Con) and three experimental groups. Type 2 diabetes mellitus (T2DM) was induced in the experimental groups via a high-fat diet followed by a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 30 mg/kg body weight. After T2DM induction, groups were assigned as sedentary (DM), subjected to 8 weeks of treadmill exercise training (Ex), or exercise training combined with 8-week cycloRGDyk treatment (ExRg). Upon completion of the last training session, all rats were euthanized and samples of fasting blood and soleus muscle were collected for analysis using ELISA, immunofluorescence, RT-qPCR, and Western blotting. Statistical differences between groups were analyzed using one-way ANOVA, and differences between two groups were assessed using t-tests. Our findings demonstrate that exercise training markedly ameliorated hyperglycaemia, hyperlipidaemia, and insulin resistance in diabetic rats (p < 0.05). It also mitigated the disarranged morphology and inflammation of skeletal muscle associated with T2DM (p < 0.05). Crucially, exercise training suppressed muscular excessive mitochondrial fission in the soleus muscle of diabetic rats (p < 0.05), and enhanced irisin and p-AMPK levels significantly (p < 0.05). However, exercise-induced irisin and p-AMPK expression were inhibited by cycloRGDyk treatment (p < 0.05). Furthermore, the administration of CycloRGDyk blocked the effects of exercise training in reducing excessive mitochondrial fission and inflammation in the soleus muscle of diabetic rats, as well as the positive effects of exercise training on improving hyperlipidemia and insulin sensitivity in diabetic rats (p < 0.05). These results indicate that regular exercise training effectively ameliorates insulin resistance and glucolipid metabolic dysfunction, and reduces inflammation in skeletal muscle. These benefits are partially mediated by reductions in mitochondrial fission through the irisin/AMPK signalling pathway.

Keywords:  Diabetes; Exercise training; Inflammation; Irisin; Mitochondrial fission

DOI:  https://doi.org/10.1038/s41598-024-61415-6
Mol Nutr Food Res. 2024 May 07. e2300347

Nutritional Strategies for Muscle Atrophy: Current Evidence and Underlying Mechanisms.

Yuntian Shen, Chen Zhang, Chaolun Dai, Yijie Zhang, Kexin Wang, Zihui Gao, Xin Chen, Xiaoming Yang, Hualin Sun, Xinlei Yao, Lingchi Xu, Hua Liu.

  Skeletal muscle can undergo detrimental changes in various diseases, leading to muscle dysfunction and atrophy, thus severely affecting people's lives. Along with exercise, there is a growing interest in the potential of nutritional support against muscle atrophy. This review provides a brief overview of the molecular mechanisms driving skeletal muscle atrophy and summarizes recent advances in nutritional interventions for preventing and treating muscle atrophy. The nutritional supplements include amino acids and their derivatives (such as leucine, β-hydroxy, β-methylbutyrate, and creatine), various antioxidant supplements (like Coenzyme Q10 and mitoquinone, resveratrol, curcumin, quercetin, Omega 3 fatty acids), minerals (such as magnesium and selenium), and vitamins (such as vitamin B, vitamin C, vitamin D, and vitamin E), as well as probiotics and prebiotics (like Lactobacillus, Bifidobacterium, and 1-kestose). Furthermore, the study discusses the impact of a combined approach involving nutritional support and physical therapy to prevent muscle atrophy, suggests appropriate multi-nutritional and multi-modal interventions based on individual conditions to optimize treatment outcomes, and enhances the recovery of muscle function for patients. By understanding the molecular mechanisms behind skeletal muscle atrophy and implementing appropriate interventions, it is possible to enhance the recovery of muscle function and improve patients' quality of life.

Keywords:  antioxidants; molecular mechanisms; muscle atrophy; nutritional support; sarcopenia

DOI:  https://doi.org/10.1002/mnfr.202300347
Physiol Res. 2024 Apr 30. 73(2): 273-284

Beneficial Effects of High-Intensity Interval Training and Dietary Changes Intervention on Hepatic Fat Accumulation in HFD-Induced Obese Rats.

X-M Yuan, M-Q Xiang, Y Ping, P-W Zhang, Y-T Liu, X-W Liu, J Wei, Q Tang, Y Zhang.

Lifestyle intervention encompassing nutrition and physical activity are effective strategies to prevent progressive lipid deposition in the liver. This study aimed to explore the effect of dietary change, and/or high-intensity interval training (HIIT) on hepatic lipid accumulation in high fat diet (HFD)-induced obese rats. We divided lean rats into lean control (LC) or HIIT groups (LH), and obese rats into obese normal chow diet (ND) control (ONC) or HIIT groups (ONH) and obese HFD control (OHC) or HIIT groups (OHH). We found that dietary or HIIT intervention significantly decreased body weight and the risk of dyslipidemia, prevented hepatic lipid accumulation. HIIT significantly improved mitochondrial fatty acid oxidation through upregulating mitochondrial enzyme activities, mitochondrial function and AMPK/PPARalpha/CPT1alpha pathway, as well as inhibiting hepatic de novo lipogenesis in obese HFD rats. These findings indicate that dietary alone or HIIT intervention powerfully improve intrahepatic storage of fat in diet induced obese rats. Keywords: Obesity, Exercise, Diet, Mitochondrial function, Lipid deposition.
Circulation. 2024 May 07. 149(19): 1490-1492

Unlocking Pathways That Improve Cardiac Function in Chronic Heart Failure: Are Ketones the Key?

Satyam Sarma, Jason R B Dyck.



Keywords:  Editorials; heart failure; ketones

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.069256
Phys Act Nutr. 2024 Mar;28(1): 1-6

Effects of post-exercise intake of exogenous lactate on energy substrate utilization at rest.

Taeho Kim, Deunsol Hwang, Sunghwan Kyun, Inkwon Jang, Sung-Woo Kim, Hun-Young Park, Kiwon Lim, Charyong Kim, Jisu Kim.

  PURPOSE: This study investigated the effects of exogenous lactate intake on energy metabolism during 1 h of rest after acute exercise.METHODS: Eight-week-old ICR mice were randomly divided into four groups: SED (no treatment), EXE (exercise only), LAC (post-exercise oral lactate administration), and SAL (post-exercise saline administration) (n=8 per group). The exercise intensity was at VO2max 80% at 25 m/min and 15° slope for 50 min. After acute exercise, the LAC and SAL groups ingested lactate and saline orally, respectively, and were allowed to rest in a chamber. Energy metabolism was measured for 1 h during the resting period.
RESULTS: LAC and SAL group mice ingested lactate and saline, respectively, after exercise and the blood lactate concentration was measured 1 h later through tail blood sampling. Blood lactate concentration was not significantly different between the two groups. Energy metabolism measurements under stable conditions revealed that the respiratory exchange ratio in the LAC group was significantly lower than that in the SAL group. Additionally, carbohydrate oxidation in the LAC group was significantly lower than that in the SAL group at 10-25 min. No significant difference was observed in the fat oxidation level between the two groups.
CONCLUSION: We found that post-exercise lactate intake modified the respiratory exchange ratio after 1 h of rest. In addition, acute lactate ingestion inhibits carbohydrate oxidation during the post-exercise recovery period.

Keywords:  carbohydrate oxidation; excess post-exercise oxygen consumption; fat oxidation; lactate; post-exercise; resting metabolic rate

DOI:  https://doi.org/10.20463/pan.2024.0001
iScience. 2024 May 17. 27(5): 109699

The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.

Megan Noble, Danielle M Colussi, Murray Junop, Peter B Stathopulos.

  The mitochondrial calcium (Ca2+) uniporter (MCU) complex is regulated via integration of the MCU dominant negative beta subunit (MCUb), a low conductance paralog of the main MCU pore forming protein. The MCU amino (N)-terminal domain (NTD) also modulates channel function through cation binding to the MCU regulating acidic patch (MRAP). MCU and MCUb have high sequence similarities, yet the structural and functional roles of MCUb-NTD remain unknown. Here, we report that MCUb-NTD exhibits α-helix/β-sheet structure with a high thermal stability, dependent on protein concentration. Remarkably, MCU- and MCUb-NTDs heteromerically interact with ∼nM affinity, increasing secondary structure and stability and structurally perturbing MRAP. Further, we demonstrate MCU and MCUb co-localization is suppressed upon NTD deletion concomitant with increased mitochondrial Ca2+ uptake. Collectively, our data show that MCU:MCUb NTD tight interactions are promoted by enhanced regular structure and stability, augmenting MCU:MCUb co-localization, lowering mitochondrial Ca2+ uptake and implicating an MRAP-sensing mechanism.

Keywords:  Cell biology; Structural biology

DOI:  https://doi.org/10.1016/j.isci.2024.109699