bims-kimdis 2024-02-11 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–02–11
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic diet for epilepsy and obesity: Is it the same?
Sex-Specific Effects of Ketogenic Diet on Anxiety-like Behavior and Neuroimmune Response in C57Bl/6J Mice.
Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
Acute ketone supplementation in the absence of muscle glycogen utilization: Insights from McArdle disease.
The impact of ketogenic diet on drug-resistant epilepsy in children: A comprehensive review and meta-analysis.
Ketone supplementation dampens subjective and objective responses to alcohol: evidence from a preclinical rat study and a randomized, cross-over trial in healthy volunteers.
Effect of exogenous and endogenous ketones on respiratory exchange ratio and glucose metabolism in healthy subjects.
The impact of microbiota and ketogenic diet interventions in the management of drug-resistant epilepsy.
GDF15 is a major determinant of ketogenic diet-induced weight loss.
Celecoxib ameliorates diabetic sarcopenia by inhibiting inflammation, stress response, mitochondrial dysfunction, and subsequent activation of the protein degradation systems.
Effect of ketogenic diet on blood pressure: A GRADE-Assessed systematic review and meta-analysis of randomized controlled trials.
Circulating ketone bodies and mortality in heart failure: a community cohort study.
Targeting NLRP3 Inflammasome: Structure, Function, and Inhibitors.
Data on mitochondrial respiratory function in skeletal muscle of adult male mice in response to 3-weeks heat stress.
Interplay of Mitochondria and Diabetes: Unveiling Novel Therapeutic Strategies.
Ablation of skeletal muscle estrogen receptor alpha impairs contractility in male mice.
Does early time-restricted eating reduce body weight and preserve fat-free mass in adults? A systematic review and meta-analysis of randomized controlled trials.
Resistance training does not increase myocellular garbage dumps: A pilot study on lipofuscin in skeletal muscle fibers of resistance trained young men.
Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).
Can the Heart Get an Overuse Sports Injury?
Understanding immunity and exercise in the context of cerebral palsy.
Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.

Nutr Metab Cardiovasc Dis. 2024 Jan 14. pii: S0939-4753(24)00016-4. [Epub ahead of print]

Ketogenic diet for epilepsy and obesity: Is it the same?

A Tagliabue, M Armeno, K A Berk, M Guglielmetti, C Ferraris, J Olieman, E van der Louw.

  The term "ketogenic diet" (KD) is used for a wide variety of diets with diverse indications ranging from obesity to neurological diseases, as if it was the same diet. This terminology is confusing for patients and the medical and scientific community. The term "ketogenic" diet implies a dietary regimen characterized by increased levels of circulating ketone bodies that should be measured in blood (beta-hydroxybutyrate), urine (acetoacetate) or breath (acetone) to verify the "ketogenic metabolic condition". Our viewpoint highlights that KDs used for epilepsy and obesity are not the same; the protocols aimed at weight loss characterized by low-fat, low-CHO and moderate/high protein content are not ketogenic by themselves but may become mildly ketogenic when high calorie restriction is applied. In contrast, there are standardized protocols for neurological diseases treatment for which ketosis has been established to be part of the mechanism of action. Therefore, in our opinion, the term ketogenic dietary therapy (KDT) should be reserved to the protocols considered for epilepsy and other neurological diseases, as suggested by the International Study Group in 2018. We propose to adjust the abbreviations in VLCHKD for Very Low CarboHydrate Ketogenic Diet and VLEKD for Very Low Energy Ketogenic Diet, to clarify the differences in dietary composition. We recommend that investigators describe the researchers describing efficacy or side effects of KDs, to clearly specify the dietary protocol used with its unique acronym and level of ketosis, when ketosis is considered as a component of the diet's mechanism of action.

Keywords:  Epilepsy; Ketogenic diet; Obesity; Very low calorie ketogenic diet; Very low carbohydrates ketogenic diet

DOI:  https://doi.org/10.1016/j.numecd.2024.01.014
J Nutr Biochem. 2024 Feb 02. pii: S0955-2863(24)00024-X. [Epub ahead of print] 109591

Sex-Specific Effects of Ketogenic Diet on Anxiety-like Behavior and Neuroimmune Response in C57Bl/6J Mice.

Mohit Kumar, Babita Bhatt, Chitralekha Gusain, Nayan Mahajan, Mahendra Bishnoi.

  The ketogenic diet (KD) has been shown to reduce anxiety and enhance cognitive functions. However, the sex-specific effects of KD on anxiety-like behavior and the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are unelucidated. This study investigated the sex-specific effects of KD on anxiety-like behavior and the neuroimmune response in the prefrontal cortex (PFC) and hippocampus of male and female C57BL/6J mice. Animals were fed either a control diet (CD- 17% fat, 65% carb, 18% protein) or a KD (80% fat, 5% carb, 15% protein) for four weeks. KD increased the levels of circulating β-hydroxybutyrate (BHB) both in males and females however, PFC BHB levels were found to be elevated only in KD males. However, KD did not affect the behavior of females but improved motor abilities and reduced anxiety levels in males. KD suppressed the mRNA expression of the putative microglial markers (Cd68, P2ry12, Nox2) and induced morphological changes in the male PFC microglia. A sex-specific decrease in IL1β and an increase in IL-10 levels was found in the PFC of KD males. A similar trend was observed in the hippocampus of males where KD reduced the mRNA expression of P2ry12, Il1β and cFos. Additionally, BHB increased the production of IL-10 whereas it decreased the production of IL1β by human microglia in in-vitro conditions. In summary, these results demonstrate that the anxiolytic and motor function enhancement abilities of KD are male-specific. Reduced pro-inflammatory and improved anti-inflammatory factors in the male PFC and hippocampus may underlie these effects.

Keywords:  Anxiety; Ketone bodies; Neuroinflammation; Precision nutrition; Sex differences; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109591
Cell Metab. 2024 Feb 06. pii: S1550-4131(24)00007-X. [Epub ahead of print]36(2): 422-437.e8

Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.

Ashley S Williams, Scott B Crown, Scott P Lyons, Timothy R Koves, Rebecca J Wilson, Jordan M Johnson, Dorothy H Slentz, Daniel P Kelly, Paul A Grimsrud, Guo-Fang Zhang, Deborah M Muoio.

  Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.

Keywords:  acylcarnitines; beta-oxidation; fiber type; intermittent fasting; ketones; metabolic flux; mitochondria; proteomics; striated muscles; time-restricted feeding

DOI:  https://doi.org/10.1016/j.cmet.2024.01.007
Clin Nutr. 2024 Jan 26. pii: S0261-5614(24)00036-0. [Epub ahead of print]43(3): 692-700

Acute ketone supplementation in the absence of muscle glycogen utilization: Insights from McArdle disease.

Pedro L Valenzuela, Alfredo Santalla, Lidia B Alejo, Asunción Bustos, Laureano M Ozcoidi, Laura Castellote-Bellés, Roser Ferrer-Costa, Mónica Villarreal-Salazar, María Morán, David Barranco-Gil, Tomàs Pinós, Alejandro Lucia.

   BACKGROUND & AIMS: Ketone supplementation is gaining popularity. Yet, its effects on exercise performance when muscle glycogen cannot be used remain to be determined. McArdle disease can provide insight into this question, as these patients are unable to obtain energy from muscle glycogen, presenting a severely impaired physical capacity. We therefore aimed to assess the effects of acute ketone supplementation in the absence of muscle glycogen utilization (McArdle disease).
METHODS: In a randomized cross-over design, patients with an inherited block in muscle glycogen breakdown (i.e., McArdle disease, n = 8) and healthy controls (n = 7) underwent a submaximal (constant-load) test that was followed by a maximal ramp test, after the ingestion of a placebo or an exogenous ketone ester supplement (30 g of D-beta hydroxybutyrate/D 1,3 butanediol monoester). Patients were also assessed after carbohydrate (75 g) ingestion, which is currently considered best clinical practice in McArdle disease.
RESULTS: Ketone supplementation induced ketosis in all participants (blood [ketones] = 3.7 ± 0.9 mM) and modified some gas-exchange responses (notably increasing respiratory exchange ratio, especially in patients). Patients showed an impaired exercise capacity (-65 % peak power output (PPO) compared to controls, p < 0.001) and ketone supplementation resulted in a further impairment (-11.6 % vs. placebo, p = 0.001), with no effects in controls (p = 0.268). In patients, carbohydrate supplementation resulted in a higher PPO compared to ketones (+21.5 %, p = 0.001) and a similar response was observed vs. placebo (+12.6 %, p = 0.057).
CONCLUSIONS: In individuals who cannot utilize muscle glycogen but have a preserved ability to oxidize blood-borne glucose and fat (McArdle disease), acute ketone supplementation impairs exercise capacity, whereas carbohydrate ingestion exerts the opposite, beneficial effect.

Keywords:  Carbohydrates; Glycogenosis; Ketone bodies; Metabolism; Performance

DOI:  https://doi.org/10.1016/j.clnu.2024.01.026
Ir J Med Sci. 2024 Feb 05.

The impact of ketogenic diet on drug-resistant epilepsy in children: A comprehensive review and meta-analysis.

Muhammad Saqlain Mustafa, Muhammad Ashir Shafique, Bilal Aheed, Farheen Ashraf, Syed Muhammad Sinaan Ali, Muhammad Faheem Iqbal, Abdul Haseeb.

  The ketogenic diet (KD), characterized by high-fat and low-carbohydrate intake, is currently gaining widespread popularity as a treatment for drug-resistant epilepsy (DRE). In addition to the traditional ketogenic diet, several variants have been introduced to enhance compliance and flexibility, such as the modified Atkins diet (MAD) and the low glycemic index diet (LGID). These adaptations aim to provide patients with more manageable and sustainable options while harnessing the potential therapeutic benefits of DRE. The objective of this study is to evaluate the efficacy and safety of the KD in pediatric patients who exhibit DRE. In this study, we conducted a thorough review of existing literature by searching Cochrane, Embase, Medline, and PubMed. Our approach involved predefined criteria for data extraction and the assessment of study quality. Eleven RCTs with 788 participants were included in this study. The pooled effect estimates revealed a significant association between dietary interventions and seizure frequency reduction of > 50% (OR 6.68, 96% CI 3.52, 12.67) and > 90% (OR 4.37, 95% CI 2.04, 9.37). Dietary interventions also increased the odds of achieving seizure freedom (OR 4.13, 95% CI 1.61, 10.60). The common adverse effects included constipation (39.07%) and vomiting (10%). In conclusion, dietary interventions, notably the KD, hold promise for pediatric DRE, reducing seizures and achieving freedom. These non-pharmacological options improve the quality of life of non-responsive and non-surgical patients. The KD has emerged as a potential therapeutic approach. Further research is needed to address the limitations and investigate their long-term effects.

Keywords:  Drug-resistant epilepsy; Epilepsy; Ketogenic diet; Low glycemic index diet; Modified Atkins diet; Nutrition; Pediatrics; Seizure

DOI:  https://doi.org/10.1007/s11845-024-03622-8
Int J Neuropsychopharmacol. 2024 Feb 05. pii: pyae009. [Epub ahead of print]

Ketone supplementation dampens subjective and objective responses to alcohol: evidence from a preclinical rat study and a randomized, cross-over trial in healthy volunteers.

Xinyi Li, Zhenhao Shi, Dustin Todaro, Timothy Pond, Juliana Byanyima, Sianneh Vesslee, Rishika Reddy, Ravi Prakash Reddy Nanga, Gabriel Kass, Vijay Ramchandani, Henry R Kranzler, Janaina C M Vendruscolo, Leandro F Vendruscolo, Corinde E Wiers.

   BACKGROUND: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown.
METHODS: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-β-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 min prior to an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration (BrAC) and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 min after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 min later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 min after alcohol exposure.
RESULTS: In humans, the intake of KS prior to alcohol significantly blunted BrAC and BAL, reduced ratings of liking and wanting more ketones/alcohol, and increased disliking the effects that they were feeling. In rats, KS reduced BAL more than either allulose or water.
CONCLUSION: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.

Keywords:  Ketone supplements; alcohol intoxication; alcohol sensitivity; alcohol use disorder; nutritional ketosis

DOI:  https://doi.org/10.1093/ijnp/pyae009
Am J Physiol Cell Physiol. 2024 Feb 05.

Effect of exogenous and endogenous ketones on respiratory exchange ratio and glucose metabolism in healthy subjects.

Rebecca Dörner, Franziska Anna Hägele, Manfred James Müller, Ulrike Seidel, Gerald Rimbach, Anja Bosy-Westphal.

  This study examined the effect of exogenous ketones (KB) on oxygen consumption (VO2), carbon dioxide production (VCO2), and glucose metabolism. The data were compared with the effects of endogenous ketonemia during both, a ketogenic diet or fasting. Eight healthy individuals (24.1 ±2.5 years, BMI 24.3 ±3.1 kg/m²) participated in a cross-over intervention study and were studied in a whole-room indirect calorimeter (WRIC) to assess macronutrient oxidation following four 24h-interventions: isocaloric controlled mixed diet (ISO), ISO supplemented with ketone salts (38.7 g beta hydroxy-butyrate/d, EXO), isocaloric ketogenic diet (KETO) and total fasting (FAST). A physical activity level of 1.65 was obtained. In addition to plasma KB, 24h C-peptide and KB excretion rates in the urine and postprandial glucose and insulin levels were measured. While 24h-KB excretion increased in response to KETO and FAST, there was a modest increase in response to EXO only (p<0.05). When compared to ISO, VO2 significantly increased in KETO (p<0.01) and EXO (p<0.001), while there was no difference in FAST. VCO2 increased in EXO but decreased in KETO (both p<0.01) and FAST (p<0.001), resulting in 24h respiratory exchange ratios (RER) of 0.828 ±0.024 (ISO) and 0.811 ±0.024 (EXO) (p<0.05). In response to EXO there were no differences in basal and postprandial glucose and insulin levels, as well as in insulin sensitivity. When compared to ISO, EXO, and KETO, FAST increased HOMA-B (all p<0.05). In conclusion, at energy balance exogenous ketone salts decreased respiratory exchange ratio without affecting glucose tolerance.

Keywords:  glucose metabolism; insulin sensitivity; ketone salts; respiratory exchange ratio

DOI:  https://doi.org/10.1152/ajpcell.00429.2023
Acta Physiol (Oxf). 2024 Feb 05. e14104

The impact of microbiota and ketogenic diet interventions in the management of drug-resistant epilepsy.

Laura Diaz-Marugan, Andrina Rutsch, Angela M Kaindl, Francesca Ronchi.

   AIM: Drug-resistant epilepsy (DRE) is a neurological disorder characterized by uncontrolled seizures. It affects between 10%-40% of the patients with epilepsy worldwide. Drug-resistant patients have been reported to have a different microbiota composition compared to drug-sensitive patients and healthy controls. Importantly, fecal microbiota transplantations (FMTs), probiotic and dietary interventions have been shown to be able to reduce seizure frequency and improve the quality of life in drug-resistant patients. The classic ketogenic diet (KD) and its modifications may reduce seizures in DRE in some patients, whereas in others they do not. The mechanisms mediating the dietary effects remain elusive, although it is known that gut microbes play an important role in transmitting dietary effects to the host. Indeed, specific commensal microbes differ even between responders and non-responders to KD treatment.
METHODS: In this narrative mini-review, we summarize what is known about the gut microbiota changes and ketogenic diets with special focus on patients with DRE.
RESULTS AND CONCLUSIONS: By highlighting unanswered questions and by suggesting future research directions, we map the route towards future improvement of successful DRE therapy.

Keywords:  diet; drug-resistant; epilepsy; gut microbiota; gut-brain axis; ketogenic diets

DOI:  https://doi.org/10.1111/apha.14104
Cell Metab. 2024 Feb 06. pii: S1550-4131(24)00004-4. [Epub ahead of print]36(2): 454-456

GDF15 is a major determinant of ketogenic diet-induced weight loss.

Jun Feng Lu, Meng Qing Zhu, Bo Xia, Na Na Zhang, Xiao Peng Liu, Huan Liu, Rui Xin Zhang, Jun Ying Xiao, Hui Yang, Ying Qi Zhang, Xiao Miao Li, Jiang Wei Wu.

DOI: https://doi.org/10.1016/j.cmet.2024.01.004
Front Pharmacol. 2024 ;15 1344276

Celecoxib ameliorates diabetic sarcopenia by inhibiting inflammation, stress response, mitochondrial dysfunction, and subsequent activation of the protein degradation systems.

Chunyan Deng, Chunfeng Lu, Kexin Wang, Mengyuan Chang, Yuntian Shen, Xiaoming Yang, Hualin Sun, Xinlei Yao, Chunjian Qiu, Feng Xu.

  Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear. Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy. Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles. Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.

Keywords:  celecoxib; diabetic sarcopenia; inflammation; oxidative stress; protein degradation systems

DOI:  https://doi.org/10.3389/fphar.2024.1344276
Nutr Metab Cardiovasc Dis. 2023 Dec 12. pii: S0939-4753(23)00486-6. [Epub ahead of print]

Effect of ketogenic diet on blood pressure: A GRADE-Assessed systematic review and meta-analysis of randomized controlled trials.

Mohammad Reza Amini, Moein Askarpour, Hamid Ghalandari, Mohammad Gholizadeh, Hamed Pouraram.

   AIMS: Cardiovascular diseases (CVDs) are major causes of mortality around the world. High blood pressure (BP) or hypertension is one of the most significant predisposing factors to CVDs. Ketogenic diets (KDs) have been the center of attention for their possible health benefits. The aim of this analysis is to study the impact of KDs on BP through the existing literature.
DATA SYNTHESIS: We investigated the impact of KDs on systolic and diastolic blood pressures (SBP and DBP) conducted in the format of randomized controlled trials (RCTs). Four online databases (PubMed/Medline, SCOPUS, Cochrane Library, and Google Scholar) were searched from inception up to November 2022. Subgroup analyses were carried out to find the sources of heterogeneities. Twenty-three RCTs with 1664 participants were identified. KDs did not exert any significant impacts on SBP (WMD: -0.87 mmHg, 95% CI: -2.05, 0.31) nor DBP (WMD: -0.11 mmHg, 95% CI -1.14, 0.93). Subgroup analyses did not reveal any further information. Also, non-linear dose-response analysis could not detect any associations between the percentage of calorie intake from fat in the KD format and BP levels.
CONCLUSION: KDs do not seem to be effective in improving BP. Nonetheless, further investigations are recommended to examine the proportion of fat intake needed to induce favorable clinical impacts.

Keywords:  Blood pressure; Hypertension; Ketogenic diet; Meta-analysis

DOI:  https://doi.org/10.1016/j.numecd.2023.12.004
Front Cardiovasc Med. 2024 ;11 1293901

Circulating ketone bodies and mortality in heart failure: a community cohort study.

Rebecca O Oyetoro, Katherine M Conners, Jungnam Joo, Sarah Turecamo, Maureen Sampson, Anna Wolska, Alan T Remaley, James D Otvos, Margery A Connelly, Nicholas B Larson, Suzette J Bielinski, Maryam Hashemian, Joseph J Shearer, Véronique L Roger.

   Background: The relationship between ketone bodies (KB) and mortality in patients with heart failure (HF) syndrome has not been well established.
Objectives: The aim of this study is to assess the distribution of KB in HF, identify clinical correlates, and examine the associations between plasma KB and all-cause mortality in a population-based HF cohort.
Methods: The plasma KB levels were measured by nuclear magnetic resonance spectroscopy. Multivariable linear regression was used to examine associations between clinical correlates and KB levels. Proportional hazard regression was employed to examine associations between KB (represented as both continuous and categorical variables) and mortality, with adjustment for several clinical covariates.
Results: Among the 1,382 HF patients with KB measurements, the median (IQR) age was 78 (68, 84) and 52% were men. The median (IQR) KB was found to be 180 (134, 308) μM. Higher KB levels were associated with advanced HF (NYHA class III-IV) and higher NT-proBNP levels (both P < 0.001). The median follow-up was 13.9 years, and the 5-year mortality rate was 51.8% [95% confidence interval (CI): 49.1%-54.4%]. The risk of death increased when KB levels were higher (HRhigh vs. low group 1.23; 95% CI: 1.05-1.44), independently of a validated clinical risk score. The association between higher KB and mortality differed by ejection fraction (EF) and was noticeably stronger among patients with preserved EF.
Conclusions: Most patients with HF exhibited KB levels that were consistent with those found in healthy adults. Elevated levels of KB were observed in patients with advanced HF. Higher KB levels were found to be associated with an increased risk of death, particularly in patients with preserved EF.

Keywords:  biomarkers; epidemiology; heart failure; ketone bodies; mortality

DOI:  https://doi.org/10.3389/fcvm.2024.1293901
Curr Med Chem. 2024 Jan 02.

Targeting NLRP3 Inflammasome: Structure, Function, and Inhibitors.

Shengying Lou, Miaolian Wu, Sunliang Cui.

  Inflammasomes are multimeric protein complexes that can detect various phys-iological stimuli and danger signals. As a result, they perform a crucial function in the in-nate immune response. The NLRP3 inflammasome, as a vital constituent of the inflam-masome family, is significant in defending against pathogen invasion and preserving cell-homeostasis. NLRP3 inflammasome dysregulation is connected to various pathological conditions, including inflammatory diseases, cancer, and cardiovascular and neurodegen-erative diseases. This profile makes NLRP3 an applicable target for treating related dis-eases, and therefore, there are rising NLRP3 inhibitors disclosed for therapy. Herein, we summarized the updated advances in the structure, function, and inhibitors of NLRP3 in-flammasome. Moreover, we aimed to provide an overview of the existing products and fu-ture directions for drug research and development.

Keywords:  NLRP3; drug discovery; function; inflammasome; inhibitor

DOI:  https://doi.org/10.2174/0109298673289984231127062528
Data Brief. 2024 Apr;53 110091

Data on mitochondrial respiratory function in skeletal muscle of adult male mice in response to 3-weeks heat stress.

Rikuhide Koma, Tatsuki Matsumoto, Ayaka Yamazaki, Tsubasa Shibaguchi, Thomas Jue, Kazumi Masuda.

  Chronic heat stress induces mitochondrial adaptation in skeletal muscle. However, the effect of chronic heat stress on the respiratory function per mitochondria in skeletal muscle has not been well studied. Here, the present study reports on the effect of 3-weeks heat stress on muscle mitochondrial respiration using male C57BL/6JJ mice at age 21 weeks. Mice were randomly assigned to either the control group (n = 6) or passive heat group (n = 6). After 3-weeks of heat stress, the right triceps surae was removed and used for biochemical analysis. Protein expression was assessed by immunoblotting. Mitochondrial respiratory function was measured by Oxygraph-2k. The study also shows the impact of the heat stress on daily feeding, body weight, muscle weight, and protein expression of heat shock proteins (heat-response marker).

Keywords:  Isolated mitochondria; Mitochondrial oxygen consumption; Oxygraph-2k; Triceps surae

DOI:  https://doi.org/10.1016/j.dib.2024.110091
Mitochondrion. 2024 Feb 06. pii: S1567-7249(24)00008-4. [Epub ahead of print] 101850

Interplay of Mitochondria and Diabetes: Unveiling Novel Therapeutic Strategies.

Kristina Xiao Liang.

The interplay between mitochondrial function and diabetes has gained significant attention due to its crucial role in the pathogenesis and progression of the disease. Mitochondria, known as the cellular powerhouses, are essential for glucose metabolism. Dysfunction of these organelles has been implicated in the development of insulin resistance and beta-cell failure, both prominent features of diabetes. This comprehensive review explores the intricate mechanisms involved, including the generation of reactive oxygen species and the impact of mitochondrial DNA mutations. Moreover, the review delves into emerging therapeutic strategies that specifically target mitochondria, such as mitochondria-targeted antioxidants, agents promoting mitochondrial biogenesis, and compounds modulating mitochondrial dynamics. The potential of these novel approaches is critically evaluated, taking into account their benefits and limitations, to provide a well-rounded perspective. Ultimately, this review emphasizes the importance of advancing our understanding of mitochondrial biology to revolutionize the treatment of diabetes.

DOI: https://doi.org/10.1016/j.mito.2024.101850
J Appl Physiol (1985). 2024 Feb 08.

Ablation of skeletal muscle estrogen receptor alpha impairs contractility in male mice.

Brian P Sullivan, Brittany C Collins, Shawna L McMillin, Elise Toussaint, Clara Z Stein, Espen E Spangenburg, Dawn A Lowe.

  Estradiol and estrogen receptor α (ERα) have been shown to be important for the maintenance of skeletal muscle strength in females, however little is known about the roles of estradiol and ERα in male muscle. The purpose of this study was to determine if skeletal muscle ERα is required for optimal contractility in male mice. We hypothesize that reduced ERα in skeletal muscle impairs contractility in male mice. Skeletal muscle specific knockout (skmERαKO) male mice exhibited reduced strength across multiple muscles and several contractile parameters related to force generation and kinetics compared to wildtype littermates (skmERαWT). Isolated EDL muscle specific isometric tetanic force, peak twitch force, peak concentric and peak eccentric forces, as well as the maximal rates of force development and relaxation were 11-21% lower in skmERαKO compared to skmERαWT mice. In contrast, isolated soleus muscles from skmERaKO mice were not affected. In vivo peak torque of the anterior crural muscles were 20% lower in skmERαKO compared to skmERαWT mice. Muscle masses, contractile protein contents, fiber types, phosphorylation of the myosin regulatory light chain, and caffeine-elicited force did not differ between muscles of skmERαKO and skmERαWT mice suggesting that strength deficits were not due to size, composition, or calcium release components of muscle contraction. These results indicate that in male mice reduced skeletal muscle ERα blunts contractility to a magnitude similar to that previously reported in females, however, the mechanism may be sexually dimorphic.

Keywords:  Estradiol; Strength; knockout; physiology; sex differences

DOI:  https://doi.org/10.1152/japplphysiol.00714.2023
Diabetes Metab Syndr. 2024 Feb 05. pii: S1871-4021(24)00013-4. [Epub ahead of print]18(2): 102952

Does early time-restricted eating reduce body weight and preserve fat-free mass in adults? A systematic review and meta-analysis of randomized controlled trials.

Mengyu He, Bo Li, Ming Li, Shan Gao.

   BACKGROUND: This meta-analysis evaluated whether weight loss caused by early time-restricted eating could promote fat mass loss while preserving fat-free mass, thereby leading to improvements in inflammation and metabolic health.
METHODS: Relevant randomized controlled trials (RCTs) published up to March 28, 2023, were identified in six databases, including PubMed, Web of Science, and Embase.
RESULTS: We initially screened 1279 articles, thirteen RCTs with 859 patients were ultimately included. Compared with nontime-restricted eating, early time-restricted eating significantly reduced body weight (-1.84 kg [-2.28, -1.41]; I2 = 56 %; P < 0.00001), fat mass (-1.10 kg [-1.47, -0.74]; I2 = 42 %; P < 0.00001), waist circumstance (-3.21 cm [-3.90, -2.51]; I2 = 43 %; P < 0.00001), visceral fat area (-9.76 cm2 [-13.76, -5.75]; I2 = 2 %; P < 0.00001), and inflammation as measured by tumour necrosis factor-α (-1.36 pg/mL [-2.12, -0.60]; I2 = 42 %; P < 0.001). However, early time-restricted eating did not lead to a significant change in fat-free mass (-0.56 kg [-1.16, 0.03]; I2 = 59 %; P = 0.06). Subgroup analysis showed that the early time-restricted eating of the 16:08 (fasting-time versus eating-time) strategy had a superior effect on preserving fat-free mass (-0.25 kg [-0.68, 0.18]; I2 = 0 %; P = 0.25) while significantly reducing body weight (-1.60 kg [-2.09, -1.11]; I2 = 0 %; P < 0.001) and improving metabolic outcomes.
CONCLUSIONS: Early time-restricted eating, especially 16:08 strategy, appears to be an effective strategy to decrease body weight, fat mass, abdominal obesity and inflammation, but less likely to decrease fat-free mass.

Keywords:  Early time restricted eating; Fat mass; Fat-free mass; Inflammation; Meta-analysis

DOI:  https://doi.org/10.1016/j.dsx.2024.102952
Physiol Rep. 2024 Feb;12(3): e15922

Resistance training does not increase myocellular garbage dumps: A pilot study on lipofuscin in skeletal muscle fibers of resistance trained young men.

Daniel Jacko, Lukas Masur, Kirill Schaaf, Jonas Zacher, Käthe Bersiner, Markus de Marées, Wilhelm Bloch, Sebastian Gehlert.

  Lipofuscin (LF) is an intracellular aggregate associated with proteostatic impairments, especially prevalent in nondividing skeletal muscle fibers. Reactive oxygen species (ROS) drive LF-formation. Resistance training (RT) improves muscle performance but also increases ROS production, potentially promoting LF-formation. Thus, we aimed to investigate if RT of a mesocycle duration increases LF-formation in type-I and II muscle fibers and whether RT increases the antioxidant capacity (AOC) in terms of SOD1 and SOD2 content. An intervention group (IG) performed 14 eccentrically accented RT-sessions within 7 weeks. Vastus lateralis muscle biopsies were collected before and after the intervention from IG as well as from a control group (CG) which refrained from RT for the same duration. LF was predominantly found near nuclei, followed by membrane-near and a minor amount in the fiber core, with corresponding spot sizes. Overall, LF-content was higher in type-I than type-II fibers (p < 0.05). There was no increase in LF-content in type-I or IIA fibers, neither for the IG following RT nor for the CG. The same is valid for SOD1/2. We conclude that, in healthy subjects, RT can be safely performed, without adverse effects on increased LF-formation.

Keywords:  SOD; exercise; fiber types; human skeletal muscle; lipofuscin

DOI:  https://doi.org/10.14814/phy2.15922
J Pharm Sci. 2024 Feb 05. pii: S0022-3549(24)00041-8. [Epub ahead of print]

Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).

Itsumi Sato, Mitsue Hibino, Atsuhito Takeda, Hideyoshi Harashima, Yuma Yamada.

  Numerous mitochondria are present in skeletal muscle cells. Muscle disease and aging impair mitochondrial functioning in the skeletal muscle. However, there have been few reports of therapeutic intervention via drug delivery to mitochondria owing to methodological difficulties. We surmised that mitochondrial activation is associated with improved skeletal muscle function. In this study, we attempted to activate the mitochondrial respiratory capacity in rat skeletal muscle cells (L6 cells) by delivering Coenzyme Q10 (CoQ10), a mitochondrial functional activator, to mitochondria using MITO-Porter, a nanoparticle that facilitates mitochondria-targeted drug delivery. Cellular uptake was confirmed by measuring the amount of fluorescence-modified MITO-Porter taken up by cells using flow cytometry. Intracellular dynamics of MITO-Porter was observed using confocal laser scanning microscopy. Mitochondrial function was assessed by measuring the mitochondrial oxygen consumption rate using an extracellular flux analyzer. The results indicated MITO-Porter-assisted delivery of CoQ10 to the mitochondria activated mitochondrial respiratory capacity in L6 cells. We believe that our results indicate the possibility of skeletal muscle therapy using mitochondrial drug delivery.

Keywords:  Drug delivery system; Lipid Nanoparticle (LNP); Liposome; Microfluidics; Muscle; Nanoparticle; Nanotechnology

DOI:  https://doi.org/10.1016/j.xphs.2024.01.020
NEJM Evid. 2023 Jan;2(1): EVIDra2200175

Can the Heart Get an Overuse Sports Injury?

Paul D Thompson, Thijs M H Eijsvogels, Jonathan H Kim.

Can the Heart Get an Overuse Sports Injury?Recent studies suggest that vigorous endurance exercise increases markers of cardiomyocyte injury and that lifelong endurance exercise may increase myocardial scarring, coronary artery atherosclerosis, AF, and aortic dilatation. This review summarizes the evidence linking these conditions with physical exertion and an approach to their management.

DOI: https://doi.org/10.1056/EVIDra2200175
Dev Med Child Neurol. 2024 Feb 08.

Understanding immunity and exercise in the context of cerebral palsy.

Tammy Strickland.

DOI: https://doi.org/10.1111/dmcn.15880
Cells. 2024 Jan 29. pii: 248. [Epub ahead of print]13(3):

Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.

Teresa Cunha-Oliveira, Liliana Montezinho, Rui F Simões, Marcelo Carvalho, Elisabete Ferreiro, Filomena S G Silva.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.

Keywords:  amyotrophic lateral sclerosis; mitochondria-targeted therapies; mitochondrial dysfunction; motor neuron degeneration; neurodegeneration; pathological mechanisms; therapeutic interventions

DOI:  https://doi.org/10.3390/cells13030248