bims-kimdis 2023-05-21 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–05–21
twenty-six papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants.
Ketogenic diet protects MPTP-induced mouse model of Parkinson's disease via altering gut microbiota and metabolites.
Association between ß-hydroxybutyrate plasma concentrations after hypocaloric ketogenic diets and changes in body composition.
Ketogenic diet promotes the proliferation of oligodendrocyte precursor cells in ME region by activating fatty acid oxidation.
Analysis of the efficacy and safety of inpatient and outpatient initiation of KD for the treatment of pediatric refractory epilepsy using generalized estimating equations.
Acute Ketone Monoester Supplementation Impairs 20-min Time-Trial Performance in Trained Cyclists: A Randomized, Crossover Trial.
Exploring mitochondrial morphology in skeletal muscle: Implications for highly trained individuals.
Intermittent exogenous ketosis: permissive or stimulatory for skeletal muscle angiogenesis in response to endurance training overload?
Difficulties in the implementation of the ketogenic diet in adult patients with refractory epilepsy.
Long-term ketogenic diet therapy improves mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS): A case report.
A new frontier for fat: dietary palmitic acid induces innate immune memory.
Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice.
Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1.
Molecular clocks, satellite cells, and skeletal muscle regeneration.
Role of Nutritional Supplements on Gut-Muscle Axis Across Age: a Mini-Review.
Sirtuins at the Crossroads between Mitochondrial Quality Control and Neurodegenerative Diseases: Structure, Regulation, Modifications, and Modulators.
Mitochondrial dysfunction in aging.
TXNIP contributes to induction of pro-inflammatory phenotype and caspase-3 activation in astrocytes during Alzheimer's diseases.
Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.
Metabolism, inflammation, and cardiovascular diseases from basic research to clinical practice.
FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice.
High-intensity interval training in the form of isometric contraction improves fatigue resistance in dystrophin-deficient muscle.
NLRP3 inflammasome-driven IL-1β and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy.
Butyrate limits inflammatory macrophage niche in NASH.
In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.
Retained Metabolic Flexibility of the Failing Human Heart.

Clin Nutr ESPEN. 2023 Jun;pii: S2405-4577(23)00092-X. [Epub ahead of print]55 292-299

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants.

Franziska A Hägele, Rebecca Dörner, Jana Koop, Marie Lübken, Ulrike Seidel, Gerald Rimbach, Manfred J Müller, Anja Bosy-Westphal.

   BACKGROUND & AIMS: Oral ketone supplements may mimic the beneficial effects of endogenous ketones on energy metabolism as β-hydroxybutyrate has been proposed to increase energy expenditure and improve body weight regulation. Therefore, our objective was to compare the effects of a one-day isocaloric ketogenic diet, fasting and supplementation with ketone salts on energy expenditure and appetite perception.
METHODS: Eight healthy young adults (4 women, 4 men, age 24 ± 3 years, BMI 24.3 ± 3.1 kg/m2) participated in a randomized cross-over trial with four 24 h-interventions in a whole room indirect calorimeter at a physical activity level of 1.65: (i) total fasting (FAST), (ii) isocaloric ketogenic diet (3.1% energy from carbohydrates (CHO), KETO), (iii) isocaloric control diet (47.4% energy from CHO, ISO), and (iv) ISO supplemented with 38.7 g/d ketone salts (exogenous ketones, EXO). Effects on serum ketone levels (15 h-iAUC), energy metabolism (total energy expenditure, TEE; sleeping energy expenditure, SEE; macronutrient oxidation) and subjective appetite were measured.
RESULTS: Compared to ISO, ketone levels were considerably higher with FAST and KETO and little higher with EXO (all p > 0.05). Total and sleeping energy expenditure did not differ between ISO, FAST and EXO whereas KETO increased TEE (+110 ± 54 kcal/d vs. ISO, p < 0.05) and SEE (+201 ± 90 kcal/d vs. ISO, p < 0.05). CHO oxidation was slightly decreased with EXO compared to ISO (-48 ± 27 g/d, p < 0.05) resulting in a positive CHO balance (p < 0.05). No differences between the interventions were found for subjective appetite ratings (all p > 0.05).
CONCLUSION: A 24 h-ketogenic diet may contribute to maintain a neutral energy balance by increasing energy expenditure. Exogenous ketones in addition to an isocaloric diet did not improve regulation of energy balance.
CLINICAL TRIAL REGISTRATION: NCT04490226 https://clinicaltrials.gov/.

Keywords:  Appetite control; Energy balance; Energy expenditure; Ketogenic diet

DOI:  https://doi.org/10.1016/j.clnesp.2023.03.025
MedComm (2020). 2023 Jun;4(3): e268

Ketogenic diet protects MPTP-induced mouse model of Parkinson's disease via altering gut microbiota and metabolites.

Ziying Jiang, Xinyu Wang, Haoqiang Zhang, Jian Yin, Peiqing Zhao, Qingqing Yin, Zhenfu Wang.

  The ketogenic diet (KD) is a low-carbohydrate, high-fat regime that is protective against neurodegenerative diseases. However, the impact of KD on Parkinson's disease (PD) and its mechanisms remains unclear. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was fed with KD for 8 weeks. Motor function and dopaminergic neurons were evaluated. Inflammation in the brain, plasma, and colon tissue were also measured. Fecal samples were assessed by 16S rDNA gene sequencing and untargeted metabolomics. We found that KD protected motor dysfunction, dopaminergic neuron loss, and inflammation in an MPTP mouse model of PD. 16S rDNA sequencing revealed that MPTP administration significantly increased Citrobacter, Desulfovibrio, and Ruminococcus, and decreased Dubosiella, whereas KD treatment reversed the dysbiosis. Meanwhile, KD regulated the MPTP-induced histamine, N-acetylputrescine, d-aspartic acid, and other metabolites. Fecal microbiota transplantation using feces from the KD-treated mice attenuated the motor function impairment and dopaminergic neuron loss in antibiotic-pretreated PD mice. Our current study demonstrates that KD played a neuroprotective role in the MPTP mouse model of PD through the diet-gut microbiota-brain axis, which may involve inflammation in the brain and colon. However, future research is warranted to explore the explicit anti-inflammatory mechanisms of the gut-brain axis in PD models fed with KD.

Keywords:  Parkinson's disease; gut microbiota; inflammation; ketogenic diet; metabolites

DOI:  https://doi.org/10.1002/mco2.268
J Nutr. 2023 May 12. pii: S0022-3166(23)37603-X. [Epub ahead of print]

Association between ß-hydroxybutyrate plasma concentrations after hypocaloric ketogenic diets and changes in body composition.

Martins C, Nymo S, Aukan Mi, Roekenes Ja, Coutinho Sr, Hunter Gr, B A Gower.

   BACKGROUND: Early studies show that ketogenic diets (KDs) lead to preferential loss of fat mass (FM), while preserving fat-free mass (FFM). Additionally, animal data supports the anticatabolic effects of DL-3-hydroxybutyrate. From our knowledge a potential association between ß-hydroxybutyrate (ßHB) plasma concentrations and changes in body composition has never been explored.
OBJECTIVE: The main aim of this analysis was to determine if ßHB plasma concentrations, following hypocaloric KDs, were associated with FM and FFM changes in men and women with obesity.
METHODS: Data from 199 individuals (BMI= 36.6±4.3 kg/m2; age= 43.6±9.8 years; 82 men) were collated from three weight loss studies employing common measures of body composition (air displacement plethysmography) and ßHB plasma concentration (ELISA). The association between ßHB and weight, FM and FFM loss (kg), and %FFM loss (%FFML) was investigated with Spearman correlation. Multivariable linear regression was used to determine if ßHB was a significant predictor of the changes in anthropometric variables, after adjusting for confounding factors.
RESULTS: ßHB was not associated with FFML (% or kg), but a weak positive association was seen with FM loss (r=0.182, P=0.01, n=199) and a trend with weight loss (r=0.128, P=0.072, n=199). ßHB was a significant predictor of both weight and FM loss (kg), after adjusting for age, sex, baseline BMI, and intervention study.
CONCLUSION: The magnitude of ketosis is not associated with FFM preservation. However, the higher the level of ketosis, the greater the weight and FM loss. Further studies are needed to confirm these findings and to explore the mechanisms involved.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01834859, NCT04051190, NCT02944253.

Keywords:  fat mass; fat-free mass; ketogenic diets; weight loss; ß-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.tjnut.2023.05.010
Yi Chuan. 2023 May 20. 45(5): 425-434

Ketogenic diet promotes the proliferation of oligodendrocyte precursor cells in ME region by activating fatty acid oxidation.

Ben Wang, Si Li, Qing-Feng Wu, Wen-Hui Mu.

  Hypothalamic median eminence (ME) is a potential niche for neurons and oligodendrocytes, and trophic factors may regulate hypothalamic function by inducing cellular changes in the ME region. To determine whether diet-induced plasticity exists in hypothalamic stem cells dormant under physiological conditions, we used a combination of a normal diet, a high-fat diet, and a ketogenic diet (a low-carb, high-fat diet) to compare the proliferation of tanycytes (TCs) and oligodendrocyte precursor cells (OPCs) in the ME area of mice under the different diets. The results showed that the ketogenic diet could induce and promote the proliferation of OPCs in the ME area, and blocking the fatty acid oxidation program could inhibit the proliferation of OPCs induced by a ketogenic diet. This study preliminarily revealed the diet-induced effect on OPCs in the ME region and provided enlightenment for further study on the function of OPCs in the ME region.

Keywords:  hypothalamus; ketogenic diet; median eminence; oligodendrocyte precursor cells

DOI:  https://doi.org/10.16288/j.yczz.23-026
Front Neurol. 2023 ;14 1146349

Analysis of the efficacy and safety of inpatient and outpatient initiation of KD for the treatment of pediatric refractory epilepsy using generalized estimating equations.

Wei Li, Xiaoyan Hao, Wei Gu, Chao Liang, Fulai Tu, Le Ding, Xiaopeng Lu, Jianxiang Liao, Hu Guo, Guo Zheng, Chunfeng Wu.

   Objective: To compare the efficacy and safety of inpatient and outpatient initiation ketogenic diet (KD) protocol of pediatric refractory epilepsy.
Methods: Eligible children with refractory epilepsy were randomly assigned to receive KD with inpatient and outpatient initiation. The generalized estimation equation (GEE) model was used to analyze the longitudinal variables of seizure reduction, ketone body, weight, height, body mass index (BMI), and BMI Z-score at different follow-up times between the two groups.
Results: Between January 2013 and December 2021, 78 and 112 patients were assigned to outpatient and inpatient KD initiation groups, respectively. There were no statistical differences between the two groups based on baseline demographics and clinical characteristics (all Ps > 0.05). The GEE model indicated that the rate of reduction of seizures≥50% in the outpatient initiation group was higher than that of the inpatient initiation group (p = 0.049). A negative correlation was observed between the seizure reduction and blood ketone body at 1, 6, and 12 months (all Ps < 0.05). There were no significant differences in height, weight, BMI, and BMI Z-score between the two groups over the 12-month period by the GEE models (all Ps > 0.05). Adverse events were reported by 31 patients (43.05%) in the outpatient KD initiation group and 46 patients (42.20%) in the inpatient KD initiation group, but these differences were not statistically significant (p = 0.909).
Conclusion: Our study shows that outpatient KD initiation is a safe and effective treatment for children with refractory epilepsy.

Keywords:  generalized estimating equations; inpatient initiation; ketogenic diet; outpatient initiation; pediatric; refractory epilepsy

DOI:  https://doi.org/10.3389/fneur.2023.1146349
Int J Sport Nutr Exerc Metab. 2023 Apr 25. 1-8

Acute Ketone Monoester Supplementation Impairs 20-min Time-Trial Performance in Trained Cyclists: A Randomized, Crossover Trial.

Devin G McCarthy, Jack Bone, Matthew Fong, Phillippe J M Pinckaers, William Bostad, Douglas L Richards, Luc J C van Loon, Martin J Gibala.

  Acute ketone monoester (KE) supplementation can alter exercise responses, but the performance effect is unclear. The limited and equivocal data to date are likely related to factors including the KE dose, test conditions, and caliber of athletes studied. We tested the hypothesis that mean power output during a 20-min cycling time trial (TT) would be different after KE ingestion compared to a placebo (PL). A sample size of 22 was estimated to provide 80% power to detect an effect size dz of 0.63 at an alpha level of .05 with a two-tailed paired t test. This determination considered 2.0% as the minimal important difference in performance. Twenty-three trained cyclists (N = 23; peak oxygen uptake: 65 ± 12 ml·kg-1 min-1; M ± SD), who were regularly cycling >5 hr/week, completed a familiarization trial followed by two experimental trials. Participants self-selected and replicated their diet and exercise for ∼24 hr before each trial. Participants ingested either 0.35 g/kg body mass of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate KE or a flavor-matched PL 30 min before exercise in a randomized, triple-blind, crossover manner. Exercise involved a 15-min warm-up followed by the 20-min TT on a cycle ergometer. The only feedback provided was time elapsed. Preexercise venous [β-hydroxybutyrate] was higher after KE versus PL (2.0 ± 0.6 vs. 0.2 ± 0.1 mM, p < .0001). Mean TT power output was 2.4% (0.6% to 4.1%; mean [95% confidence interval]) lower after KE versus PL (255 ± 54 vs. 261 ± 54 W, p < .01; dz = 0.60). The mechanistic basis for the impaired TT performance after KE ingestion under the present study conditions remains to be determined.

Keywords:  acid-base balance; continuous glucose monitor; exogenous ketone; heart rate; nutritional ketosis

DOI:  https://doi.org/10.1123/ijsnem.2022-0255
J Physiol. 2023 May 18.

Exploring mitochondrial morphology in skeletal muscle: Implications for highly trained individuals.

Blair MacLeod.



Keywords:  mitochondria; mitochondrial cristae; resistance exercise; skeletal muscle; strength training; weightlifting

DOI:  https://doi.org/10.1113/JP284873
J Physiol. 2023 May 16.

Intermittent exogenous ketosis: permissive or stimulatory for skeletal muscle angiogenesis in response to endurance training overload?

Arianne Zabbal, Alyasamin Alhamwi, Benjamin M Sauvageau, Sarkis J Hannaian.



Keywords:  angiogenesis; exogenous ketones; β-hydroxybutyrate

DOI:  https://doi.org/10.1113/JP284917
Epilepsy Behav. 2023 May 14. pii: S1525-5050(23)00153-1. [Epub ahead of print]144 109234

Difficulties in the implementation of the ketogenic diet in adult patients with refractory epilepsy.

Irem Erkent, Fatma Ilgaz, Nese Dericioglu.

   BACKGROUND: Ketogenic diet therapies (KDT) are appropriate therapeutic options for pediatric and adult patients with intractable epilepsy. The application of KDT among adult patients with refractory epilepsy is limited compared to children for several reasons, including poor compliance. We present the significant reasons for the lack of adherence to KDT in our adult patients with intractable epilepsy.
METHODS: This study was conducted retrospectively in adult patients with drug-resistant epilepsy who wereofferedand accepted toimplementKDT between 2014 and 2021. Demographic and clinical data were collected via electronic health records. The eventual outcome of KDT results was obtained from the consultant dietitian. The prevalence and reasons for the failure to implement KDT were investigated. We also obtained detailed information about patients who successfully applied the KDT.
RESULTS: A total of 33 patients (18F; median age 28) who wereoffered and accepted to implement KDT were included. Baseline seizure frequency was >4 per week in 49%, and more than half of the patients used >3 anti-seizure medications (ASM). Epilepsy types were temporal in 10 (30%), extratemporal in 10 (30%), generalized in 6 (18%), and unclassified in 7 (22%) patients.Only 3 patients (9%) were able to maintain KDT in the long term. One of them (33%) benefited from this therapy.In the remaining 30 patients, the reasons for failure were inability to contact the dietitian in 5, failure to apply KDT for a particular reason in 7, inappropriate blood test results or any medical/surgical comorbidities in 6, improvement in seizure burden due to change in ASM in 5, still insufficient knowledge of KDT in 3, unresponsiveness to diet due to incorrect implementation in 1 and unidentified reasons in 3 patients.
CONCLUSIONS: A significant percentage of adult patients with refractory seizures failed to use KDTin our study(91%).Strategies to improve compliance and minimize the side effects might increase the number of drug-refractory epilepsy patients who could benefit from this therapy.

Keywords:  Adult; Compliance; Intractable epilepsy; Ketogenic diet; Outcome

DOI:  https://doi.org/10.1016/j.yebeh.2023.109234
CNS Neurosci Ther. 2023 May 19.

Long-term ketogenic diet therapy improves mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS): A case report.

Fang He, Lingqi Ye, Pu Miao, Jiong Zhou, Yao Ding, Shuang Wang.



Keywords:  MELAS syndrome; epileptic seizures; ketogenic diet

DOI:  https://doi.org/10.1111/cns.14274
Immunometabolism (Cobham). 2023 Apr;5(2): e00021

A new frontier for fat: dietary palmitic acid induces innate immune memory.

Amy L Seufert, Brooke A Napier.

  Dietary saturated fats have recently been appreciated for their ability to modify innate immune cell function, including monocytes, macrophages, and neutrophils. Many dietary saturated fatty acids (SFAs) embark on a unique pathway through the lymphatics following digestion, and this makes them intriguing candidates for inflammatory regulation during homeostasis and disease. Specifically, palmitic acid (PA) and diets enriched in PA have recently been implicated in driving innate immune memory in mice. PA has been shown to induce long-lasting hyper-inflammatory capacity against secondary microbial stimuli in vitro and in vivo, and PA-enriched diets alter the developmental trajectory of stem cell progenitors in the bone marrow. Perhaps the most relevant finding is the ability of exogenous PA to enhance clearance of fungal and bacterial burdens in mice; however, the same PA treatment enhances endotoxemia severity and mortality. Westernized countries are becoming increasingly dependent on SFA-enriched diets, and a deeper understanding of SFA regulation of innate immune memory is imperative in this pandemic era.

Keywords:  CD36; ceramide; chylomicron; epigenetics; hematopoietic stem cell; inflammation; innate immune memory; ketogenic diet; macrophages; metabolism; monocytes; oleic acid; palmitic acid; priming; saturated fatty acid; toll-like receptor; trained immunity; western diet

DOI:  https://doi.org/10.1097/IN9.0000000000000021
Life Metab. 2023 Apr;pii: load014. [Epub ahead of print]2(2):

Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice.

Patrick J Ferrara, Marisa J Lang, Jordan M Johnson, Shinya Watanabe, Kelsey L McLaughlin, J Alan Maschek, Anthony R P Verkerke, Piyarat Siripoksup, Amandine Chaix, James E Cox, Kelsey H Fisher-Wellman, Katsuhiko Funai.

  Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype (WT) male C57BL6/N mice were fed with high fat diet for 10 weeks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 weeks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2 consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

Keywords:  energy efficiency; energy expenditure; mitochondria; oxidative phosphorylation; phospholipids; weight loss

DOI:  https://doi.org/10.1093/lifemeta/load014
Oncogene. 2023 Apr 25.

Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1.

Tianxiao Mao, Fujian Qin, Mengdi Zhang, Jing Li, Jiankang Li, Maode Lai.

Colorectal cancer (CRC) ranks third in incidence and second in mortality worldwide. Metabolic disorders are known to be closely associated with CRC. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Previous work based on untargeted liquid chromatography identified 30 differential metabolites of CRC. Among them, only β-hydroxybutyrate (BHB) was elevated in CRC. Here, we first confirm the increased level of β-hydroxybutyrate by targeted metabolomic analysis using an independent cohort of 400 serum samples by UPLC-QQQ-MS/MS analysis. Using appropriate cell and animal models, we find that treatment with pathological levels of β-hydroxybutyrate expedites CRC proliferation and metastasis. Out of four major rate-limiting enzymes of ketolysis, only acetyl-coenzyme A acetyltransferase1 (ACAT1) expression is increased in paired human CRC tissues. These findings suggest probable clinical relevance for the functional implications of β-hydroxybutyrate in CRC. We demonstrate that β-hydroxybutyrate may exert its tumorigenic effects via regulation of ACAT1, due to induction of downstream isocitrate dehydrogenase1 (IDH1) acetylation. Genetic silencing of ACAT1 significantly suppresses the progression of CRC and abrogates the effects of β-hydroxybutyrate both in vitro and in vivo. Overall, this study suggests that targeting β-hydroxybutyrate and its major rate-limiting enzyme ACAT1 may provide a new avenue for therapeutic intervention in CRC.

DOI: https://doi.org/10.1038/s41388-023-02700-y
Am J Physiol Cell Physiol. 2023 May 15.

Molecular clocks, satellite cells, and skeletal muscle regeneration.

Ryan E Kahn, Sudarshan Dayanidhi, Orly Lacham-Kaplan, John A Hawley.

  Skeletal muscle comprises approximately 50% of individual body mass and plays vital roles in locomotion, heat production, and whole-body metabolic homeostasis. This tissue exhibits a robust diurnal rhythm which is under control of the suprachiasmatic nucleus (SCN) region of the hypothalamus. The SCN acts as a 'central' co-ordinator of circadian rhythms, while cell-autonomous 'peripheral' clocks are located within almost all other tissues/organs in the body. Synchronization of peripheral clocks in muscle (and other tissues) together with the central clock is crucial to ensure temporally coordinated physiology across all organ systems. By virtue of its mass, human skeletal muscle contains the largest collection of peripheral clocks, but within muscle resides a local stem cell population, satellite cells (SC's), which have their own functional molecular clock independent of the numerous muscle clocks. Skeletal muscle has a daily turnover rate of 1-2%, so the regenerative capacity of this tissue is important for whole-body homeostasis/repair and depends on successful SC myogenic progression (i.e., proliferation, differentiation and fusion). Emerging evidence suggests SC-mediated muscle regeneration may, in part, be regulated by molecular clocks involved in SC-specific diurnal transcription. Here we provide insight on molecular clock regulation of muscle regeneration/repair and provide a novel perspective on the interplay between SC-specific molecular clocks, myogenic programs, and cell cycle kinetics that underpin myogenic progression.

Keywords:  cell cycle; circadian rhythms; muscle stem cells; myogenesis; myogenic regulatory factors

DOI:  https://doi.org/10.1152/ajpcell.00073.2023
Cell Physiol Biochem. 2023 May 14. 57(3): 161-168

Role of Nutritional Supplements on Gut-Muscle Axis Across Age: a Mini-Review.

Ricardo Aparecido Baptista Nucci, Victor Abou Nehmi Filho, Wilson Jacob-Filho, José Pinhata Otoch, Ana Flávia Marçal Pessoa.

  Sarcopenia is a progressive skeletal muscle disorder associated with aging, resulting in loss of muscle mass and function. It has been linked to inflammation, oxidative stress, insulin resistance, hormonal changes (i.e. alterations in the levels or activity of hormones which can occur due to a variety of factors, including aging, stress, disease, medication, and environmental factors), and impaired muscle satellite cell activation. The gut microbiome is also essential for muscle health, and supplements such as probiotics, prebiotics, protein, creatine, and betaalanine can support muscle growth and function while also promoting gut health. Chronic low-grade inflammation is a leading cause of sarcopenia, which can activate signaling pathways that lead to muscle wasting and reduce muscle protein synthesis. Insulin resistance, hormonal changes, and impaired muscle satellite cell activation contribute to sarcopenia, and high levels of fat mass also play a role in the pathogenesis of sarcopenia. Resistance exercise and dietary supplementation have been shown to be effective treatments for sarcopenia. In addition, a combination of resistance exercise and supplementation has been shown to have a more significant beneficial effect on anthropometric and muscle function parameters, leading to a decrease in sarcopenic state. Thus, understanding the relationship between the gut microbiome and muscle metabolism is crucial for developing new treatments for sarcopenia across age groups.

Keywords:  Aging; Microbiota; Muscle; Nutrition; Prebiotics; Sarcopenia

DOI:  https://doi.org/10.33594/000000628
Aging Dis. 2023 Jun 01. 14(3): 794-824

Sirtuins at the Crossroads between Mitochondrial Quality Control and Neurodegenerative Diseases: Structure, Regulation, Modifications, and Modulators.

Hui Xu, Yi-Yang Liu, Lin-Seng Li, You-Shuo Liu.

Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes, are key regulators of life span and metabolism. In addition to acting as deacetylates, some sirtuins have the properties of deacylase, decrotonylase, adenosine diphosphate (ADP)-ribosyltransferase, lipoamidase, desuccinylase, demalonylase, deglutarylase, and demyristolyase. Mitochondrial dysfunction occurs early on and acts causally in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Sirtuins are implicated in the regulation of mitochondrial quality control, which is highly associated with the pathogenesis of neurodegenerative diseases. There is growing evidence indicating that sirtuins are promising and well-documented molecular targets for the treatment of mitochondrial dysfunction and neurodegenerative disorders by regulating mitochondrial quality control, including mitochondrial biogenesis, mitophagy, mitochondrial fission/fusion dynamics, and mitochondrial unfolded protein responses (mtUPR). Therefore, elucidation of the molecular etiology of sirtuin-mediated mitochondrial quality control points to new prospects for the treatment of neurodegenerative diseases. However, the mechanisms underlying sirtuin-mediated mitochondrial quality control remain obscure. In this review, we update and summarize the current understanding of the structure, function, and regulation of sirtuins with an emphasis on the cumulative and putative effects of sirtuins on mitochondrial biology and neurodegenerative diseases, particularly their roles in mitochondrial quality control. In addition, we outline the potential therapeutic applications for neurodegenerative diseases of targeting sirtuin-mediated mitochondrial quality control through exercise training, calorie restriction, and sirtuin modulators in neurodegenerative diseases.

DOI: https://doi.org/10.14336/AD.2022.1123
Ageing Res Rev. 2023 May 15. pii: S1568-1637(23)00114-9. [Epub ahead of print] 101955

Mitochondrial dysfunction in aging.

Ying Guo, Teng Guan, Kashfia Shafiq, Qiang Yu, Xin Jiao, Donghui Na, Meiyu Li, Guohui Zhang, Jiming Kong.

  Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of aging, the role of mitochondrial quality control (MQC) in aging is still poorly understood. A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized by-products through mitochondrial proteases and mitochondrial unfolded protein response (UPRmt). Mitochondrial-derived vesicles (MDVs) are the first line of MQC to dispose of oxidized derivatives. Besides, mitophagy helps remove partially damaged mitochondria to ensure that mitochondria are healthy and functional. Although abundant interventions on MQC have been explored, over-activation or inhibition of any type of MQC may even accelerate abnormal energy metabolism and mitochondrial dysfunction-induced senescence. This review summarizes mechanisms essential for maintaining mitochondrial homeostasis and emphasizes that imbalanced MQC may accelerate cellular senescence and aging. Thus, appropriate interventions on MQC may delay the aging process and extend lifespan.

Keywords:  Aging; mitochondrial dysfunction; mitochondrial quality control; reactive oxygen species

DOI:  https://doi.org/10.1016/j.arr.2023.101955
Redox Biol. 2023 May 06. pii: S2213-2317(23)00136-2. [Epub ahead of print]63 102735

TXNIP contributes to induction of pro-inflammatory phenotype and caspase-3 activation in astrocytes during Alzheimer's diseases.

Junhyung Kim, Jaejoon Lim, Ik Dong Yoo, Samel Park, Jong-Seok Moon.

  Neuroinflammation and oxidative stress have been implicated in the pathogenesis of Alzheimer's disease (AD). Neuroinflammation and oxidative stress are associated with neuronal death in AD. Astrocytes are linked to neuroinflammation during AD. Astrocytes are important contributors to AD progression. Although the role of thioredoxin-interacting protein (TXNIP) has been identified in inflammation and oxidative stress, the mechanism by which TXNIP regulates inflammation and oxidative stress in astrocytes during AD remains unclear. In the present study, we found that TXNIP gene levels were elevated in cerebral cortex of patients with AD. The protein levels of TXNIP were elevated in GFAP-positive astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. Our results showed that TXNIP increased expression of genes related to pro-inflammatory reactive astrocytes and pro-inflammatory cytokines and chemokines in human astrocytes. Moreover, TXNIP increased production of pro-inflammatory cytokines and chemokines in human astrocytes. TXNIP induced activation of NK-kB signaling and over-production of mitochondrial reactive oxygen species (mtROS) in human astrocytes. TXNIP also induced mitochondrial oxidative stress by reduction of mitochondrial respiration and ATP production in human astrocytes. Furthermore, elevated TXNIP levels are correlated with caspase-3 activation of GFAP-positive astrocytes in patients with AD and mouse AD. TXNIP induced mitochondria-dependent apoptosis via caspase-9 and caspase-3 activation in human astrocytes. These results suggest that TXNIP contributes to induction of pro-inflammatory phenotype and caspase-3 activation in astrocytes during AD.

Keywords:  Alzheimer’s disease; Astrocytes; Caspase-3; Inflammation; Mitochondrial oxidative stress; TXNIP

DOI:  https://doi.org/10.1016/j.redox.2023.102735
Mucosal Immunol. 2023 May 11. pii: S1933-0219(23)00036-3. [Epub ahead of print]

Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.

Anh Thu Dang, Christina Begka, Céline Pattaroni, Laura R Caley, R Andres Floto, Daniel G Peckham, Benjamin J Marsland.

  Short-chain fatty acids (SCFAs) are metabolites that are produced following microbial fermentation of dietary fibre and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways. Butyrate impacted discrete aspects of haematopoiesis in the bone marrow resulting in the accumulation of immature neutrophils. During Pseudomonas aeruginosa infection, butyrate treatment led to enhanced mobilization of neutrophils to the lungs as a result of increased CXCR2 expression by lung macrophages. Despite this increase in granulocyte numbers and their enhanced phagocytic capacity, neutrophils failed to control early bacterial growth. Butyrate reduced expression of nicotinamide adenine dinucleotide phosphate (NADPH), oxidase complex components required for reactive oxygen species (ROS) production, and reduced secondary granule enzymes, culminating in impaired bactericidal activity. These data reveal that SCFAs tune neutrophil maturation and effector function in the bone marrow under homeostatic conditions, potentially to mitigate against excessive granulocyte-driven immunopathology, but their consequently restricted bactericidal capacity impairs early control of Pseudomonas infection.

Keywords:  butyrate; hematopoiesis; lung; metabolite; neutrophil

DOI:  https://doi.org/10.1016/j.mucimm.2023.05.005
Cardiol Plus. 2023 Jan-Mar;8(1):8(1): 4-5

Metabolism, inflammation, and cardiovascular diseases from basic research to clinical practice.

Zihang Huang, Aijun Sun.

DOI: https://doi.org/10.1097/CP9.0000000000000037
Aging Biol. 2022 ;pii: 3. [Epub ahead of print]1

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice.

Mariah F Calubag, Ismail Ademi, Chung-Yang Yeh, Reji Babygirija, Heidi H Pak, Alyssa M Bhoopat, Ildiko Kasza, Cara L Green, Michelle M Sonsalla, Dudley W Lamming.

Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21-/- and wild-type control mice either ad libitum (AL) diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of Fgf21 blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.

Keywords: FGF21; beiging; calorie restriction; glucose homeostasis; metabolic health; white adipose tissue
J Physiol. 2023 May 15.

High-intensity interval training in the form of isometric contraction improves fatigue resistance in dystrophin-deficient muscle.

Nao Yamauchi, Katsuyuki Tamai, Iori Kimura, Azuma Naito, Nao Tokuda, Yuki Ashida, Norio Motohashi, Yoshitsugu Aoki, Takashi Yamada.

  Duchenne muscular dystrophy (DMD) is a genetic muscle-wasting disorder characterised by progressive muscle weakness and easy fatigability. Here we examined whether high-intensity interval training (HIIT) in the form of isometric contraction improves fatigue resistance in skeletal muscle from dystrophin-deficient mdx52 mice. Isometric HIIT was performed on plantar flexor muscles in vivo with supramaximal electrical stimulation every other day for 4 weeks (a total of 15 sessions). In the non-trained contralateral gastrocnemius muscle from mdx52 mice, the decreased fatigue resistance was associated with a reduction in the amount of PGC-1α, citrate synthase activity, mitochondrial respiratory complex II, LC3B-II/I ratio, and mitophagy-related gene expression (i.e., Pink1, parkin, Bnip3, and Bcl2l13) as well as an increase in the phosphorylation levels of Src Tyr416 and Akt Ser473, the amount of p62, and the percentage of Evans blue dye-positive area. Isometric HIIT restored all these alterations and markedly improved fatigue resistance in mdx52 muscles. Moreover, an acute bout of HIIT increased the phosphorylation levels of AMPK Thr172, ACC Ser79, Ulk1 Ser555, and Drp1 Ser616 in mdx52 muscles. Thus, our data show that HIIT with isometric contractions significantly mitigates histological signs of pathology and improves fatigue resistance in dystrophin-deficient muscles. These beneficial effects can be explained by the restoration of mitochondrial function via AMPK-dependent induction of the mitophagy program and de novo mitochondria biogenesis. KEY POINTS: Skeletal muscle fatigue is often associated with Duchenne muscular dystrophy (DMD) and leads to an inability to perform daily tasks, profoundly decreasing quality of life. We examined the effect of high-intensity interval training (HIIT) in the form of isometric contraction on fatigue resistance in skeletal muscle from the mdx52 mouse model of DMD. Isometric HIIT counteracted the reduced fatigue resistance as well as dystrophic changes in skeletal muscle of mdx52 mice. This beneficial effect could be explained by the restoration of mitochondrial function via AMPK-dependent mitochondrial biogenesis and the induction of mitophagy program in the dystrophic muscles. Abstract figure legend As a result of the loss of dystrophin, increased production of NADPH oxidase 2 (NOX2)- and mitochondria-derived reactive oxygen species (ROS) causes mitochondrial Ca2+ overload as well as an activation of Src/Akt pathway. This then leads to mitochondrial dysfunction and perturbation of mitophagy, which contribute to dystrophic pathology and decreased fatigue resistance due to accumulation of damaged mitochondria in dystrophin-deficient muscle. High-intensity interval training (HIIT) with isometric contractions mitigates dystrophic alterations and improves fatigue resistance, presumably via AMPK-dependent mitochondrial turnover; dysfunctional mitochondria are eliminated via mitophagy and replaced through de novo mitochondria biogenesis. This article is protected by copyright. All rights reserved.

Keywords:  fatigue resistance; high-intensity interval training; isometric contraction; mitochondria; muscular dystrophy

DOI:  https://doi.org/10.1113/JP284532
J Mol Cell Cardiol. 2023 May 10. pii: S0022-2828(23)00089-5. [Epub ahead of print]180 58-68

NLRP3 inflammasome-driven IL-1β and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy.

Kenta Fujimura, Tadayoshi Karasawa, Takanori Komada, Naoya Yamada, Yoshiko Mizushina, Chintogtokh Baatarjav, Takayoshi Matsumura, Kinya Otsu, Norihiko Takeda, Hiroaki Mizukami, Kazuomi Kario, Masafumi Takahashi.

  Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1β and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3-/- mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3-/- mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3-/- mice. LPS-induced SCM was also prevented in Casp1/11-/- mice, but not in Casp11mt, IL-1β-/-, IL-1α-/-, or GSDMD-/- mice. Notably, LPS-induced SCM was apparently prevented in IL-1β-/- mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1β and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM.

Keywords:  Cardiomyopathy; Cytokine, heart; Inflammation; Interleukin

DOI:  https://doi.org/10.1016/j.yjmcc.2023.05.003
Cell Death Dis. 2023 May 18. 14(5): 332

Butyrate limits inflammatory macrophage niche in NASH.

Ankita Sarkar, Priya Mitra, Abhishake Lahiri, Tanusree Das, Jit Sarkar, Sandip Paul, Partha Chakrabarti.

Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH.

DOI: https://doi.org/10.1038/s41419-023-05853-6
Int J Mol Sci. 2023 May 04. pii: 8247. [Epub ahead of print]24(9):

In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.

Federica Conte, Angel Ashikov, Rachel Mijdam, Eline G P van de Ven, Monique van Scherpenzeel, Raisa Veizaj, Seyed P Mahalleh-Yousefi, Merel A Post, Karin Huijben, Daan M Panneman, Richard J T Rodenburg, Nicol C Voermans, Alejandro Garanto, Werner J H Koopman, Hans J C T Wessels, Marek J Noga, Dirk J Lefeber.

  Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on 13C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.

Keywords:  PGM1 congenital disorder of glycosylation; PGM1 deficiency; in vitro muscle model; muscle energy homeostasis; muscle metabolic plasticity; phosphoglucomutase 1

DOI:  https://doi.org/10.3390/ijms24098247
Circulation. 2023 May 18.

Retained Metabolic Flexibility of the Failing Human Heart.

William D Watson, Peregrine G Green, Andrew J M Lewis, Per Arvidsson, Giovanni Luigi De Maria, Hakan Arheden, Einar Heiberg, William T Clarke, Christopher T Rodgers, Ladislav Valkovič, Stefan Neubauer, Neil Herring, Oliver J Rider.

   BACKGROUND: The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation by increasing oxygen efficiency of adenosine triphosphate production, with mixed results.
METHODS: To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo2), invasive arteriovenous sampling and pressure-volume loops were performed (n=9).
RESULTS: At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; P=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; P=0.009).Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; P=0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; P<0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism.
CONCLUSIONS: Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.

Keywords:  adenosine triphosphate; heart failure; magnetic resonance spectroscopy; metabolism

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.062166