bims-kimdis 2024-05-19 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–05–19
twelve papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic Diet Protects from Experimental Colitis in a Mouse Model Regardless of Dietary Fat Source.
Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults, a randomized, parallel arm, double-blind, placebo-controlled, pilot study.
Ketogenic Diet in the Treatment of Epilepsy.
Specifically formulated ketogenic, low carbohydrate, and carnivore diets can prevent migraine: a perspective.
Exogenous erythropoietin increases hematological status, fat oxidation, and aerobic performance in males following prolonged strenuous training.
AMPK as a mediator of tissue preservation: time for a shift in dogma?
Fecal Microbiota Transplantation Attenuates Frailty via Gut-Muscle Axis in Old Mice.
MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
Is it time for a genuine placebo-controlled trial on effects of vitamin D?
Skeletal muscle fitness and physiology as determinants of firefighter performance and safety: a narrative review.
Mitochondrial dysfunction: mechanisms and advances in therapy.
Serine synthesis controls mitochondrial biogenesis in macrophages.

Nutrients. 2024 Apr 29. pii: 1348. [Epub ahead of print]16(9):

Ketogenic Diet Protects from Experimental Colitis in a Mouse Model Regardless of Dietary Fat Source.

Lotta Luiskari, Jere Lindén, Markku Lehto, Hanne Salmenkari, Riitta Korpela.

  While ketogenic diets (KDs) may have potential as adjunct treatments for gastrointestinal diseases, there is little knowledge on how the fat source of these diets impacts intestinal health. The objective of this study was to investigate how the source of dietary fat of KD influences experimental colitis. We fed nine-week-old male C57BL/6J mice (n = 36) with a low-fat control diet or KD high either in saturated fatty acids (SFA-KD) or polyunsaturated linoleic acid (LA-KD) for four weeks and then induced colitis with dextran sodium sulfate (DSS). To compare the diets, we analyzed macroscopic and histological changes in the colon, intestinal permeability to fluorescein isothiocyanate-dextran (FITC-dextran), and the colonic expression of tight junction proteins and inflammatory markers. While the effects were more pronounced with LA-KD, both KDs markedly alleviated DSS-induced histological lesions. LA-KD prevented inflammation-related weight loss and the shortening of the colon, as well as preserved Il1b and Tnf expression at a healthy level. Despite no significant between-group differences in permeability to FITC-dextran, LA-KD mitigated changes in tight junction protein expression. Thus, KDs may have preventive potential against intestinal inflammation, with the level of the effect being dependent on the dietary fat source.

Keywords:  colitis; dietary fat; intestinal inflammation; ketogenic diet

DOI:  https://doi.org/10.3390/nu16091348
medRxiv. 2024 May 05. pii: 2024.05.03.24306699. [Epub ahead of print]

Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults, a randomized, parallel arm, double-blind, placebo-controlled, pilot study.

Brianna J Stubbs, Elizabeth B Stephens, Chatura Senadheera, Sawyer Peralta, Stephanie Roa-Diaz, Laura Alexander, Wendie Silverman-Martin, Thelma Y Garcia, Michi Yukawa, Jenifer Morris, Traci M Blonquist, James B Johnson, John C Newman.

Objectives: Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this trial was to determine tolerability and safety of KE ingestion in older adults.
Design: Randomized, placebo-controlled, double-blinded, parallel-arm trial, with a 12-week intervention period ( NCT05585762 ).
Setting: General community, Northern California, USA.
Participants: Community-dwelling older adults, independent in activities of daily living, with no unstable acute medical conditions (n=30) were randomized and n=23 (M= 14, F=9) completed the protocol.
Intervention: Participants were randomly allocated to consume either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil.
Measurements: Tolerability was assessed using a composite score from a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events.
Results: There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n =2 (14.3% [90% CI = 2.6 - 38.5]); PLA n=1 (7.1% [90% CI = 0.4 - 29.7]). Dropouts numbered four in the PLA group and two in the KE group. A greater number of symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2 - 12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group.
Conclusions: This KE was safe and well-tolerated in healthy older adults. These results provide a foundation for use of KEs in aging research.
Highlights: Ketones esters induce ketosis without dietary changes and may target aging biologyStudies of ketone esters were limited in duration and focused on younger adultsWe found ketone esters were safe and tolerable for 12 weeks in healthy older adults.

DOI: https://doi.org/10.1101/2024.05.03.24306699
Nutrients. 2024 Apr 24. pii: 1258. [Epub ahead of print]16(9):

Ketogenic Diet in the Treatment of Epilepsy.

Kinga Borowicz-Reutt, Marlena Krawczyk, Julia Czernia.

  Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Keywords:  KD; efficacy; epilepsy; ketogenic diet; safety; seizure

DOI:  https://doi.org/10.3390/nu16091258
Front Nutr. 2024 ;11 1367570

Specifically formulated ketogenic, low carbohydrate, and carnivore diets can prevent migraine: a perspective.

Angela A Stanton.

  This article presents a hypothesis explaining the cause of migraines, suggesting that electrolyte imbalance, specifically a lack of sufficient sodium in the extracellular space of sensory neurons, leads to failed action potentials. The author argues that migraines are triggered when sodium channels fail to initiate action potentials, preventing communication between neurons. The article discusses the evolutionary perspective of the migraine brain, stating that migraineurs have a hypersensitive brain with more sensory neuronal connections, making them more reactive to environmental stimuli and in need of more minerals for the increased sensory neuronal communication. Since glucose is often used to reduce serum hypernatremia, it follows that a high carbohydrate diet reduces sodium availability for use in the brain, causing an electrolyte imbalance. Low carbohydrate diets, such as ketogenic, low carb-high fat (LCHF), and carnivore (all animal products), can be beneficial for migraineurs by reducing/eliminating carbohydrate intake, thereby increasing sodium availability. In support, many research papers and some anecdotal evidences are referred to. The article concludes by proposing lifestyle modifications, such as dietary changes and sodium intake management. These will provide migraineurs with a long-term healthy metabolic foundation helping them to maintain strong nutritional adherence and with that aiding continued proper neuronal functioning and migraine free life.

Keywords:  LCHF; carbohydrate; carnivore; hypersensory; ketogenic; metabolic; migraine; salt

DOI:  https://doi.org/10.3389/fnut.2024.1367570
Physiol Rep. 2024 May;12(10): e16038

Exogenous erythropoietin increases hematological status, fat oxidation, and aerobic performance in males following prolonged strenuous training.

Devin J Drummer, Julie L McNiff, Emily E Howard, Jess A Gwin, Christopher T Carrigan, Nancy E Murphy, Marques A Wilson, Julia Michalak, Benjamin J Ryan, James P McClung, Stefan M Pasiakos, Lee M Margolis.

  This study investigated the effects of EPO on hemoglobin (Hgb) and hematocrit (Hct), time trial (TT) performance, substrate oxidation, and skeletal muscle phenotype throughout 28 days of strenuous exercise. Eight males completed this longitudinal controlled exercise and feeding study using EPO (50 IU/kg body mass) 3×/week for 28 days. Hgb, Hct, and TT performance were assessed PRE and on Days 7, 14, 21, and 27 of EPO. Rested/fasted muscle obtained PRE and POST EPO were analyzed for gene expression, protein signaling, fiber type, and capillarization. Substrate oxidation and glucose turnover were assessed during 90-min of treadmill load carriage (LC; 30% body mass; 55 ± 5% V̇O2peak) exercise using indirect calorimetry, and 6-6-[2H2]-glucose PRE and POST. Hgb and Hct increased, and TT performance improved on Days 21 and 27 compared to PRE (p < 0.05). Energy expenditure, fat oxidation, and metabolic clearance rate during LC increased (p < 0.05) from PRE to POST. Myofiber type, protein markers of mitochondrial biogenesis, and capillarization were unchanged PRE to POST. Transcriptional regulation of mitochondrial activity and fat metabolism increased from PRE to POST (p < 0.05). These data indicate EPO administration during 28 days of strenuous exercise can enhance aerobic performance through improved oxygen carrying capacity, whole-body and skeletal muscle fat metabolism.

Keywords:  V̇O2peak; hematocrit; hemoglobin; mitochondria; substrate oxidation

DOI:  https://doi.org/10.14814/phy2.16038
Nat Rev Endocrinol. 2024 May 17.

AMPK as a mediator of tissue preservation: time for a shift in dogma?

Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.

DOI: https://doi.org/10.1038/s41574-024-00992-y
Aging Dis. 2024 Apr 13.

Fecal Microbiota Transplantation Attenuates Frailty via Gut-Muscle Axis in Old Mice.

Mengpei Zhu, Yumei Huang, Ziwen Wang, Ze Jin, Jiali Cao, Qiangqiang Zhong, Zhifan Xiong.

Targeting adverse pathogenic gut microbiota regulation through fecal microbiota transplantation (FMT) may restore health and has been validated in some aging-related diseases. However, the mechanisms of the gut microbiota's role in frailty and whether modulation of the gut microbiota can treat age-related frailty remain largely unknown. To assess the effects of FMT on frailty, we used bidirectional fecal microbiota transplantation in young and old mice. We demonstrated that fecal bacteria transplanted from old mice into young mice reduced body weight and grip strength (p=0.002), and led to elevated inflammatory factors in young mice, but had no significant effect on intestinal barrier function. Notably, FMT treatment in older mice not only improved frailty (grip strength: p=0.036, low physical activity: p=0.020, running speed: p=0.048, running time: p=0.058, frailty score: p=0.027) and muscle mass, but also improved intestinal ecological imbalances, intestinal barrier function, and systemic inflammation (serum TNF-α: p=0.002, and IL-6: p<0.001). KEGG enrichment analysis of fecal metabolites showed that FMT may ameliorate frailty through the sphingolipid metabolism pathway. In addition, aged mice given FMT treatment showed a significant increase in the abundance of SCFA-producing bacteria and increased levels of short-chain fatty acids (butyric acid: p=0.084, propionic acid: p=0.028). Subsequent further verification found that FMT ameliorating frailty may be achieved through SCFAs metabolism. Another mechanism study found that FMT reduces lipopolysaccharide levels (p<0.001), thereby inhibiting the TLR4/NF-κB signaling pathway and its downstream pro-inflammatory products. Therefore, regulating SCFAs metabolism by altering gut microbial composition and targeting the gut-muscle axis with LPS/TLR4 pathways may be potential strategies to treat frailty in older adults.

DOI: https://doi.org/10.14336/AD.2024.0321
Circ Res. 2024 May 15.

MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.

Barbara Roman, Yusuf Mastoor, Junhui Sun, Hector Chapoy Villanueva, Gabriela Hinojosa, Danielle Springer, Julia C Liu, Elizabeth Murphy.

   BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.
METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.
RESULTS: Knock out MICU3 hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, overexpression of MICU3 hearts exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, overexpression of MICU3 animals exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in overexpression of MICU3 hearts compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.
CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.

Keywords:  calcium; cardiomegaly; echocardiography; mitochondria; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324026
J Clin Endocrinol Metab. 2024 May 17. pii: dgae345. [Epub ahead of print]

Is it time for a genuine placebo-controlled trial on effects of vitamin D?

Lise Sofie Bislev, Lars Rejnmark.



Keywords:  Vitamin D; balance; muscle; omega-3 fatty acids; physical performance

DOI:  https://doi.org/10.1210/clinem/dgae345
Ergonomics. 2024 May 14. 1-11

Skeletal muscle fitness and physiology as determinants of firefighter performance and safety: a narrative review.

Ryan A Gordon, Matthew L Sokoloski, Emily L Zumbro, Chris J Irvine, Michael Oldham, Natalie Morgan.

  Firefighters routinely perform tasks that are reliant on their muscular fitness, which includes muscular strength, power and endurance. Separately, firefighters can present with unique skeletal muscle physiology characteristics due to the strenuous nature of this occupation. This review aims to summarise muscular fitness and physiology as determinants of a firefighter's ability to perform occupation-specific tasks, identify the relevance of both muscular fitness and physiology to a firefighter's risk for sustaining a work-related injury, and address the contributions of muscular fitness and physiology on a firefighter's ability to recover from tasks and their readiness for performing subsequent or future tasks. The presented evidence reveals muscular fitness can determine a firefighter's capacity to perform their job effectively, while also influencing risk for occupational injury. Collectively, this review indicates exercise training emphasising improvements in muscular strength, power, and endurance (i.e. resistance training) should be encouraged in this occupation.

Keywords:  Firefighters; fitness; injuries; performance; skeletal muscle

DOI:  https://doi.org/10.1080/00140139.2024.2352719
Signal Transduct Target Ther. 2024 May 15. 9(1): 124

Mitochondrial dysfunction: mechanisms and advances in therapy.

Yao Zong, Hao Li, Peng Liao, Long Chen, Yao Pan, Yongqiang Zheng, Changqing Zhang, Delin Liu, Minghao Zheng, Junjie Gao.

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

DOI: https://doi.org/10.1038/s41392-024-01839-8
Sci Adv. 2024 May 17. 10(20): eadn2867

Serine synthesis controls mitochondrial biogenesis in macrophages.

Chuanlong Wang, Muyang Zhao, Peng Bin, Yuyi Ye, Qingyi Chen, Zhiru Tang, Wenkai Ren.

Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.

DOI: https://doi.org/10.1126/sciadv.adn2867