bims-kimdis 2024-04-07 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒04‒07
twenty papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Common and divergent molecular mechanisms of fasting and ketogenic diets.
Ketogenic diet improves alcohol withdrawal.
Diet-induced ketosis in adult patients with subacute acquired brain injury: a feasibility study.
Very low-calorie ketogenic diet (VLCKD): a therapeutic nutritional tool for acne?
A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.
Effects of ketogenic diet on weight loss parameters among obese or overweight patients with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trails.
Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate.
Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
Very low-carbohydrate and keto diet increases unhealthy cholesterol.
Ketogenic dietary therapy utilization in Kenya: A qualitative exploration of dietitian's perceptions.
β-hydroxybutyrate inhibits malignant phenotypes of prostate cancer cells through β-hydroxybutyrylation of indoleacetamide-N-methyltransferase.
Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.
PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
Endurance training and hydroxyurea have synergistic effects on muscle function and energetics in sickle cell disease mice.
NLRP3 inflammasome signalling in Alzheimer's disease.
Berberine inhibits NLRP3 inflammasome activation and proinflammatory macrophage M1 polarization to accelerate peripheral nerve regeneration.
Exercise increases TCA intermediate concentrations during low-calorie diet independent of insulin resistance among women with obesity.
Benchmarking pre-clinical heart failure with preserved ejection fraction models: can we do better?
SGLT2 Inhibitors, Functional Capacity, and Quality of Life in Patients With Heart Failure: A Systematic Review and Meta-Analysis.
How papers with doctored images can affect scientific reviews.

Trends Endocrinol Metab. 2024 Feb;pii: S1043-2760(23)00214-X. [Epub ahead of print]35(2): 125-141

Common and divergent molecular mechanisms of fasting and ketogenic diets.

Antonio Paoli, Grant M Tinsley, Mark P Mattson, Immaculata De Vivo, Ravi Dhawan, Tatiana Moro.

  Intermittent short-term fasting (ISTF) and ketogenic diets (KDs) exert overlapping but not identical effects on cell metabolism, function, and resilience. Whereas health benefits of KD are largely mediated by the ketone bodies (KBs), ISTF engages additional adaptive physiological responses. KDs act mainly through inhibition of histone deacetylases (HDACs), reduction of oxidative stress, improvement of mitochondria efficiency, and control of inflammation. Mechanisms of action of ISTF include stimulation of autophagy, increased insulin and leptin sensitivity, activation of AMP-activated protein kinase (AMPK), inhibition of the mechanistic target of rapamycin (mTOR) pathway, bolstering mitochondrial resilience, and suppression of oxidative stress and inflammation. Frequent switching between ketogenic and nonketogenic states may optimize health by increasing stress resistance, while also enhancing cell plasticity and functionality.

Keywords:  brain; fasting; ketogenic diet; ketone bodies; mitochondria; time-restricted eating

DOI:  https://doi.org/10.1016/j.tem.2023.10.001
Lab Anim (NY). 2024 Apr;53(4): 88

Ketogenic diet improves alcohol withdrawal.

Jorge Ferreira.

DOI: https://doi.org/10.1038/s41684-024-01359-6
Front Med (Lausanne). 2023 ;10 1305888

Diet-induced ketosis in adult patients with subacute acquired brain injury: a feasibility study.

Maria G P Edwards, Jens R Andersen, Derek J Curtis, Christian G Riberholt, Ingrid Poulsen.

  Background: Research in animal models on cerebral metabolism after brain injury highlights the potential benefits of ketosis in reducing secondary brain injury, but studies in humans are lacking.Aim: This study aimed to examine if a 6-week ketogenic diet intervention with added medium-chain triglycerides (MCT) was feasible in adult patients with acquired brain injury in the subacute phase, whether ketosis could be achieved and maintained, and to what extent serious adverse reactions, adverse reactions, serious adverse events, and adverse events occured.
Methods: Patients ≥18 years of age diagnosed with subacute acquired brain injury and an expectation of hospitalisation ≥6 weeks were included in the intervention group. Patients not included in the intervention group were included in a standard care reference group. The intervention consisted of a ketogenic diet supplemented with MCT to obtain a plasma concentration of β-hydroxybutyrate (BHB) ≥0.5 mmol/L. Patients who were enterally fed were given KetoCal® 2.5:1 LQ MCT Multi Fiber (Nutricia A/S, Allerød, Denmark), supplemented with Liquigen® (Nutricia A/S, Allerød, Denmark). Patients consuming oral nutrition were given KetoCal® 2.5:1 LQ MCT Multi Fiber supplemented with Liquigen®, in addition to ketogenic meals.
Results: During a 13-week inclusion period, 12 of 13 eligible patients (92% [95% CI: 67% to 99%]) were included in the intervention group, and 17 of 18 excluded patients (94% [95% CI: 74% to 99%]) were included in the reference group. Eight patients (67%) completed the 6-week intervention. It took a median of 1 day to achieve ketosis from starting a 100% MCT ketogenic diet, and it was maintained for 97% of the intervention period after ketosis was obtained. There were no serious adverse reactions to the MCT ketogenic diet, and patients experienced adverse reactions not considered serious in 9.5% of days with the intervention. The MCT ketogenic diet was accepted by patients on all intervention days, and in the two patients transitioning from enteral feeding to oral intake, there were no complications related to transitioning.
Conclusion: Intervention with MCT ketogenic diet is feasible and tolerated for 6 weeks in hospitalised adult patients with subacute acquired brain injury. Randomised controlled trials are needed to assess the benefits and harms of the MCT ketogenic diet and the effect on patients' recovery.Clinical trial registration: ClinicalTrials.gov, identifier [NCT04308577].

Keywords:  acquired brain injury (ABI); ketogenic diet (KD); ketosis; medium-chain triglycerides (MCT); stroke; subarachnoid haemorrhage (SAH); traumatic brain injury (TBI); β-hydroxybutyrate (BHB)

DOI:  https://doi.org/10.3389/fmed.2023.1305888
J Transl Med. 2024 Mar 31. 22(1): 322

Very low-calorie ketogenic diet (VLCKD): a therapeutic nutritional tool for acne?

Ludovica Verde, Evelyn Frias-Toral, Sara Cacciapuoti, Daniel Simancas-Racines, Matteo Megna, Giuseppina Caiazzo, Luca Potestio, Maria Maisto, Gian Carlo Tenore, Annamaria Colao, Silvia Savastano, Giovanna Muscogiuri, Luigi Barrea.

  BACKGROUND: Acne, a chronic inflammatory disease impacting the pilosebaceous unit, is influenced significantly by inflammation and oxidative stress, and is commonly associated with obesity. Similarly, obesity is also associated with increased inflammation and oxidation. The role of diet in acne remains inconclusive, but the very low-calorie ketogenic diet (VLCKD), known for weight loss and generating anti-inflammatory ketone bodies, presents promising potential. Despite this, the effects of VLCKD on acne remain underexplored. This study aimed to investigate the efficacy of a 45-day active phase of VLCKD in reducing the clinical severity of acne in young women with treatment-naïve moderate acne and grade I obesity.METHODS: Thirty-one women with treatment-naïve moderate acne, grade I obesity (BMI 30.03-34.65 kg/m2), aged 18-30 years, meeting inclusion/exclusion criteria, and consenting to adhere to VLCKD were recruited. Baseline and post-intervention assessments included anthropometric measurements, body composition, phase angle (PhA), trimethylamine N-oxide (TMAO) levels, and reactive oxygen metabolite derivatives (dROMs) as markers of inflammation, dysbiosis, and oxidative stress, respectively. A comprehensive dermatological examination, incorporating the Global Acne Grading System (GAGS) and the Dermatology Life Quality Index (DLQI), was conducted for all women.
RESULTS: VLCKD resulted in general improvements in anthropometric and body composition parameters. Significantly, there were significant reductions in both the GAGS score (Δ%: - 31.46 ± 9.53, p < 0.001) and the DLQI score (Δ%: - 45.44 ± 24.02, p < 0.001) after the intervention. These improvements coincided with significant decreases in TMAO (p < 0.001) and dROMs (p < 0.001) levels and a significant increase in PhA (Δ%: + 8.60 ± 7.40, p < 0.001). Changes in the GAGS score positively correlated with changes in dROMs (p < 0.001) and negatively with PhA (p < 0.001) even after adjusting for Δ% FM. Changes in the DLQI score positively correlated with changes in dROMs (p < 0.001) and negatively with PhA (p < 0.001) even after adjustment for Δ% FM.
CONCLUSION: Given the side effects of drugs used for acne, there is an increasing need for safe, tolerable, and low-cost treatments that can be used for acne disease. The 45-day active phase of VLCKD demonstrated notable improvements in acne severity, and these improvements seemed to be attributable to the known antioxidant and anti-inflammatory effects of VLCKD.

Keywords:  Acne; Diet; Inflammation; Ketogenic diet; Nutrition; Obesity; Oxidative stress; VLCKD; Very low-calorie ketogenic diet

DOI:  https://doi.org/10.1186/s12967-024-05119-5
BMC Neurol. 2024 Apr 01. 24(1): 106

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

Alexander H Choi, Melanie Delgado, Kong Y Chen, Stephanie T Chung, Amber Courville, Sara A Turner, Shanna Yang, Kayla Airaghi, Irene Dustin, Patrick McGurrin, Tianxia Wu, Mark Hallett, Debra J Ehrlich.

  BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD).OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG).
METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity.
RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups.
CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease.
TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Keywords:  Biomarker; Clinical trial; Ketogenic diet; Ketosis; Parkinson’s disease; Pilot study

DOI:  https://doi.org/10.1186/s12883-024-03603-5
Food Nutr Res. 2024 ;68

Effects of ketogenic diet on weight loss parameters among obese or overweight patients with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trails.

Nan-Nan Xing, Fang Ren, Hui Yang.

  Aim: To evaluate how effective a low carbohydrate ketogenic diet (KD) is for changing key physical measurements such as weight, waist circumference (WC), body mass index (BMI), and fat mass (FM) in women with polycystic ovary syndrome (PCOS) who were obese or overweight.Methods: Several online databases, including PubMed, Scopus, EMBASE, Cochrane Library, and Web of Science (WOS), were searched systematically to find relevant randomized controlled trials (RCTs) up until June 2023. The Q-test and I2 statistics were used to assess the level of heterogeneity among the included studies. The data were then combined using either a fixed or random effects model and presented as a weighted mean difference (WMD) along with a 95% confidence interval (CI).
Results: Of the 682 citations, 11 RCTs were included. The pooled results showed a significant decrease in the WMD of weight levels [WMD = -9.13 kg; 95% CI, -11.88, -6.39, P < 0.001; I2 = 87.23%] following KD. Moreover, KD significantly reduced BMI levels [WMD = -2.93 kg/m2; 95% CI, -3.65, -2.21, P < 0.001; I2 = 78.81%] compared to the controls. Patients with PCOS received KD demonstrated significant decrease in WC [WMD = -7.62 cm; 95% CI, -10.73, -4.50, P < 0.001; I2 = 89.17%] and FM [WMD = -5.32 kg; 95% CI, -7.29, -3.36, P < 0.001; I2 = 83.97%].
Conclusion: KD was associated with lower weight loss (WL) parameters, including weight, BMI, WC, and FM, in obese or overweight women with PCOS, highlighting the significance of physicians and nurses in taking care of the nutritional needs of overweight/obese patients with PCOS.

Keywords:  ketogenic diet; meta-analysis; obesity; polycystic ovary syndrome; weight loss

DOI:  https://doi.org/10.29219/fnr.v68.9835
J Am Heart Assoc. 2024 Apr 02. e033628

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate.

Nigopan Gopalasingam, Niels Moeslund, Kristian Hylleberg Christensen, Kristoffer Berg-Hansen, Jacob Seefeldt, Casper Homilius, Erik Nguyen Nielsen, Mie Ringgaard Dollerup, Aage K Alstrup Olsen, Mogens Johannsen, Ebbe Boedtkjer, Niels Møller, Hans Eiskjær, Lars Christian Gormsen, Roni Nielsen, Henrik Wiggers.

  BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined.METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, D- and L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D- and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics.
CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3-OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

Keywords:  3‐hydroxybutyrate; heart failure; hemodynamics; ketone; metabolism; pharmacokinetics; pressure‐volume loop

DOI:  https://doi.org/10.1161/JAHA.123.033628
Sci Adv. 2024 Apr 05. 10(14): eadl0389

Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.

Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.

The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.

DOI: https://doi.org/10.1126/sciadv.adl0389
Am J Clin Nutr. 2024 Apr;pii: S0002-9165(24)00127-8. [Epub ahead of print]119(4): 1091

Very low-carbohydrate and keto diet increases unhealthy cholesterol.

Pradnya Phalak, Abhijit Pratap, Umesh More, Mona Tilak.

DOI: https://doi.org/10.1016/j.ajcnut.2024.02.010
Epilepsy Behav Rep. 2024 ;26 100661

Ketogenic dietary therapy utilization in Kenya: A qualitative exploration of dietitian's perceptions.

Pauline Samia, Violet Naanyu, J Helen Cross, Richard Idro, Paul Boon, Jo Wilmshurst, Stanley Luchters.

  This study utilized a qualitative design to explore dietitians' perceptions regarding Ketogenic Diet Therapy (KDT) for patients with drug-resistant epilepsy in Kenya. Dietitians from Kenya were selected and consented. Audio-recorded interviews were conducted, followed by thematic analysis of verbatim transcripts to identify recurring patterns. The study enrolled 18 dietitians, fourteen of whom correctly described their understanding of KDT for managing drug-resistant epilepsy. There was a lack of confidence in their capacity to initiate the KDT with all expressing the need for further training and facilitation. Only one dietitian reported having initiated and maintained KDT. There was an overall positive view regarding KDT and willingness to implement KDT for patients with drug-resistant epilepsy. Dietitians expressed concerns regarding the availability of national policies, inadequate staffing to support families who require KDT, and the cost of implementing this intervention. Dietitians expressed interest in virtual training to enhance their understanding of KDT. Dietitians in Kenya are mostly aware of KDT utilization for the management of drug-resistant epilepsy. However, they cited poor capability and various barriers to implementation. There is a need for policies to facilitate KDT as a treatment option for the benefit of patients with drug-resistant epilepsy.

Keywords:  Dietitian; Drug-resistant epilepsy; Kenya; Ketogenic diet; Low-resource setting

DOI:  https://doi.org/10.1016/j.ebr.2024.100661
Cancer Cell Int. 2024 Mar 30. 24(1): 121

β-hydroxybutyrate inhibits malignant phenotypes of prostate cancer cells through β-hydroxybutyrylation of indoleacetamide-N-methyltransferase.

Yifan Zhang, Yunlong Li.

  BACKGROUND: Prostate cancer (PCa) is one of the most prevalent cancers in men and is associated with high mortality and disability rates. β-hydroxybutyrate (BHB), a ketone body, has received increasing attention for its role in cancer. However, its role in PCa remains unclear. This study aimed to explore the mechanism and feasibility of BHB as a treatment alternative for PCa.METHODS: Colony formation assay, flow cytometry, western blot assay, and transwell assays were performed to determine the effect of BHB on the proliferation and metastasis of PCa cells. Tumor sphere formation and aldehyde dehydrogenase assays were used to identify the impact of BHB or indoleacetamide-N-methyltransferase (INMT) on the stemness of PCa cells. N6-methyladenosine (m6A)-meRIP real-time reverse transcription polymerase chain reaction and dual luciferase assays were conducted to confirm INMT upregulation via the METTL3-m6A pathway. Co-IP assay was used to detect the epigenetic modification of INMT by BHB-mediated β-hydroxybutyrylation (kbhb) and screen enzymes that regulate INMT kbhb. Mouse xenograft experiments demonstrated the antitumor effects of BHB in vivo.
RESULTS: BHB can inhibit the proliferation, migration, and invasion of PCa cells by suppressing their stemness. Mechanistically, INMT, whose expression is upregulated by the METTL3-m6A pathway, was demonstrated to be an oncogenic gene that promotes the stem-like characteristics of PCa cells. BHB can suppress the malignant phenotypes of PCa by kbhb of INMT, which in turn inhibits INMT expression.
CONCLUSIONS: Our findings indicate a role of BHB in PCa metabolic therapy, thereby suggesting an epigenetic therapeutic strategy to target INMT in aggressive PCa.
TRIAL REGISTRATION: Not applicable.

Keywords:  INMT; Kbhb; Prostate cancer; Stemness; β-hydroxybutyrate

DOI:  https://doi.org/10.1186/s12935-024-03277-6
J Physiol. 2024 Apr 02.

Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.

Hailey A Parry, T Bradley Willingham, Kevin A Giordano, Yuho Kim, Shureed Qazi, Jay R Knutson, Christian A Combs, Brian Glancy.

  Mitochondria within skeletal muscle cells are located either between the muscle contractile apparatus (interfibrillar mitochondria, IFM) or beneath the cell membrane (subsarcolemmal mitochondria, SSM), with several structural and functional differences reported between IFM and SSM. However, recent 3D imaging studies demonstrate that mitochondria are particularly concentrated in the proximity of capillaries embedded in sarcolemmal grooves rather than in proximity to the sarcolemma itself (paravascular mitochondria, PVM). To evaluate the impact of capillary vs. sarcolemmal proximity, we compared the structure and function of skeletal muscle mitochondria located either lateral to embedded capillaries (PVM), adjacent to the sarcolemma but not in PVM pools (SSM) or interspersed between sarcomeres (IFM). Mitochondrial morphology and interactions were assessed by 3D electron microscopy coupled with machine learning segmentation, whereas mitochondrial energy conversion was assessed by two-photon microscopy of mitochondrial membrane potential, content, calcium, NADH redox and flux in live, intact cells. Structurally, although PVM and SSM were similarly larger than IFM, PVM were larger, rounder and had more physical connections to neighbouring mitochondria compared to both IFM and SSM. Functionally, PVM had similar or greater basal NADH flux compared to SSM and IFM, respectively, despite a more oxidized NADH pool and a greater membrane potential, signifying a greater activation of the electron transport chain in PVM. Together, these data indicate that proximity to capillaries has a greater impact on resting mitochondrial energy conversion and distribution in skeletal muscle than the sarcolemma alone. KEY POINTS: Capillaries have a greater impact on mitochondrial energy conversion in skeletal muscle than the sarcolemma. Paravascular mitochondria are larger, and the outer mitochondrial membrane is more connected with neighbouring mitochondria. Interfibrillar mitochondria are longer and have greater contact sites with other organelles (i.e. sarcoplasmic reticulum and lipid droplets). Paravascular mitochondria have greater activation of oxidative phosphorylation than interfibrillar mitochondria at rest, although this is not regulated by calcium.

Keywords:  energy function; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/JP286246
Stem Cell Reports. 2024 Mar 26. pii: S2213-6711(24)00079-1. [Epub ahead of print]

PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.

George Cairns, Madhavee Thumiah-Mootoo, Mah Rukh Abbasi, Melissa Gourlay, Jeremy Racine, Nikita Larionov, Alexandre Prola, Mireille Khacho, Yan Burelle.

  Maintenance of mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC), but the underlying mechanisms remain ill defined. In this study, we monitored mitophagy in MuSCS under various myogenic states and examined the role of PINK1 in maintaining regenerative capacity. Results indicate that quiescent MuSCs actively express mitophagy genes and exhibit a measurable mitophagy flux and prominent mitochondrial localization to autophagolysosomes, which become rapidly decreased during activation. Genetic disruption of Pink1 in mice reduces PARKIN recruitment to mitochondria and mitophagy in quiescent MuSCs, which is accompanied by premature activation/commitment at the expense of self-renewal and progressive loss of muscle regeneration, but unhindered proliferation and differentiation capacity. Results also show that impaired fate decisions in PINK1-deficient MuSCs can be restored by scavenging excess mitochondrial ROS. These data shed light on the regulation of mitophagy in MuSCs and position PINK1 as an important regulator of their mitochondrial properties and fate decisions.

Keywords:  fate decision; mitochondria; mitochondrial quality control; mitophagy; muscle regeneration; muscle stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2024.03.004
Blood Cells Mol Dis. 2024 Mar 29. pii: S1079-9796(24)00031-7. [Epub ahead of print]107 102853

Endurance training and hydroxyurea have synergistic effects on muscle function and energetics in sickle cell disease mice.

Constance P Michel, Laurent A Messonnier, Benoit Giannesini, Christophe Vilmen, Joevin Sourdon, Yann Le Fur, David Bendahan.

  Sickle cell disease (SCD) is an hemoglobinopathy resulting in the production of an abnormal Hb (HbS) which can polymerize in deoxygenated conditions, leading to the sickling of red blood cells (RBC). These alterations can decrease the oxygen-carrying capacity leading to impaired function and energetics of skeletal muscle. Any strategy which could reverse the corresponding defects could be of interest. In SCD, endurance training is known to improve multiples muscle properties which restores patient's exercise capacity but present reduced effects in anemic patients. Hydroxyurea (HU) can increase fetal hemoglobin production which can reduce anemia in patients. The present study was conducted to determine whether HU can improve the effects of endurance training to improve muscle function and energetics. Twenty SCD Townes mice have been trained for 8 weeks with (n = 11) or without (n = 9) HU. SCD mice muscle function and energetics were analyzed during a standardized rest-exercise-recovery protocol, using Phosphorus-31 Magnetic resonance spectroscopy (31P-MRS) and transcutaneous stimulation. The combination of training and HU specifically decreased fatigue index and PCr consumption while muscle oxidative capacity was improved. These results illustrate the potential synergistic effects of endurance training and HU on muscle function and energetics in sickle cell disease.

Keywords:  (31)P-magnetic resonance spectroscopy; Endurance training; Hydroxyurea; Sickle cell disease; Skeletal muscle

DOI:  https://doi.org/10.1016/j.bcmd.2024.102853
Neuropharmacology. 2024 Mar 31. pii: S0028-3908(24)00110-2. [Epub ahead of print] 109941

NLRP3 inflammasome signalling in Alzheimer's disease.

Róisín M McManus, Eicke Latz.

  Every year, 10 million people develop dementia, the most common of which is Alzheimer's disease (AD). To date, there is no way to prevent cognitive decline and therapies are limited. This review provides a neuroimmunological perspective on the progression of AD, and discusses the immune-targeted therapies that are in preclinical and clinical trials that may impact the development of this disease. Specifically, we look to the role of the NLRP3 inflammasome, its triggers in the brain and how its activation can contribute to the progression of dementia. We summarise the range of inhibitors targeting the NLRP3 inflammasome and its downstream pathways that are under investigation, and discuss future therapeutic perspectives for this devastating condition.

Keywords:  Alzheimer's disease; Immune-targeted therapies; Microglia; NLRP3 inflammasome; Neuroimmunology; Preclinical models

DOI:  https://doi.org/10.1016/j.neuropharm.2024.109941
Neurotherapeutics. 2024 Apr 02. pii: S1878-7479(24)00033-3. [Epub ahead of print] e00347

Berberine inhibits NLRP3 inflammasome activation and proinflammatory macrophage M1 polarization to accelerate peripheral nerve regeneration.

Jun Sun, Qiuhua Zeng, Zhimin Wu, Lixin Huang, Tao Sun, Cong Ling, Baoyu Zhang, Chuan Chen, Hui Wang.

  Berberine (BBR) has demonstrated potent anti-inflammatory effects by modulating macrophage polarization. Nevertheless, the precise mechanisms through which berberine regulates post-injury inflammation within the peripheral nerve system remain elusive. This study seeks to elucidate the role of BBR and its underlying mechanisms in inflammation following peripheral nerve injury (PNI). Adult male C57BL/6J mice subjected to PNI were administered daily doses of berberine (0, 60, 120, 180, 240 mg/kg) via gavage from day 1 through day 28. Evaluation of the sciatic function index (SFI) and paw withdrawal threshold revealed that BBR dose-dependently enhanced both motor and sensory functions. Immunofluorescent staining for anti-myelin basic protein (anti-MBP) and anti-neurofilament-200 (anti-NF-200), along with histological staining comprising hematoxylin-eosin (HE), luxol fast blue (LFB), and Masson staining, demonstrated that BBR dose-dependently promoted structural regeneration. Molecular analyses including qRT-PCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence confirmed that inactivation of the NLRP3 inflammasome by MCC950 shifted macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, while also impeding macrophage infiltration. Furthermore, BBR significantly downregulated the expression of the NLRP3 inflammasome and its associated molecules in macrophages, thereby mitigating NLRP3 inflammasome activation-induced macrophage M1 polarization and inflammation. In summary, BBR's neuroprotective effects were concomitant with the suppression of inflammation after PNI, achieved through the inhibition of NLRP3 inflammasome activation-induced macrophage M1 polarization.

Keywords:  Berberine; Inflammation; Macrophage polarization; NLRP3 inflammasome; Peripheral nerve injury

DOI:  https://doi.org/10.1016/j.neurot.2024.e00347
Physiol Rep. 2024 Apr;12(7): e15987

Exercise increases TCA intermediate concentrations during low-calorie diet independent of insulin resistance among women with obesity.

Tristan J Ragland, Steven K Malin.

  Tricarboxylic acid cycle intermediates (TCAi) have been proposed to act as myokines that influence energy metabolism. We determined if 2-weeks of low-calorie diet with interval exercise (LCD + INT) would increase TCAi more than a low-calorie diet (LCD). Twenty-three women were randomized to 2-weeks of LCD (n = 12, 48.4 ± 2.5 years, 37.8 ± 1.5 kg/m2, ~1200 kcal/d) or LCD + INT (n = 11, 47.6 ± 4.3 years, 37.9 ± 2.3 kg/m2; 60 min/d supervised INT of 3 min 90% & 50% HRpeak). TCAi and amino acids (AA) were measured at 0 min of a 75 g OGTT, while glucose, insulin, and FFA were obtained at 0, 30, 60, 90, 120, and 180 min to assess total area under the curve (tAUC180min) and insulin resistance (IR; tAUC180min of Glucose × Insulin). Fuel use (indirect calorimetry) was also collected at 0, 60, 120, and 180 min as was fitness (VO2peak) and body composition (BodPod). Treatments reduced weight (p < 0.001), fasting RER (p = 0.01), and IR (p = 0.03), although LCD + INT increased VO2peak (p = 0.02) and maintained RER tAUC180min (p = 0.05) versus LCD. Treatments increased FFA tAUC180min (p = 0.005), cis-aconitate, isocitrate, and succinate (p ≤ 0.02), as well as reduced phenylalanine and tryptophan, cysteine (p ≤ 0.005). However, LCD + INT increased malate, citrate, α-ketoglutarate, and alanine more than LCD (p ≤ 0.04). Thus, INT enhanced LCD effects on some TCAi in women with obesity independent of IR.

Keywords:  amino acids; diabetes; interval training; obesity; tricarboxylic acid cycle

DOI:  https://doi.org/10.14814/phy2.15987
Cardiovasc Res. 2024 Apr 04. pii: cvae059. [Epub ahead of print]

Benchmarking pre-clinical heart failure with preserved ejection fraction models: can we do better?

David A Kass.



Keywords:  Animal models; HFpEF; Heart failure; Human; Metabolism; Obesity

DOI:  https://doi.org/10.1093/cvr/cvae059
JAMA Netw Open. 2024 Apr 01. 7(4): e245135

SGLT2 Inhibitors, Functional Capacity, and Quality of Life in Patients With Heart Failure: A Systematic Review and Meta-Analysis.

Michael Gao, Kirtipal Bhatia, Arjun Kapoor, Juan Badimon, Sean P Pinney, Donna M Mancini, Carlos G Santos-Gallego, Anuradha Lala.

Importance: The associations of sodium glucose cotransporter-2 inhibitors (SGLT2is) with reduction in mortality and hospitalization rates in patients with heart failure (HF) are well established. However, their association with improving functional capacity and quality of life (QOL) has been variably studied and less reported.Objective: To provide evidence on the extent to which SGLT2is are associated with improvement on objective measures of functional capacity and QOL in patients living with HF.
Data Sources: The MEDLINE, EMBASE, and Cochrane databases were systematically searched for relevant articles on July 31, 2023.
Study Selection: Randomized, placebo-controlled clinical trials reporting the effect of SGLT2i on functional outcomes of exercise capacity (peak oxygen consumption [peak VO2] or 6-minute walk distance [6MWD]) and/or QOL using validated questionnaires for patients with HF were included.
Data Extraction and Synthesis: Data were extracted by 2 authors following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, and a meta-analysis using the restricted maximum likelihood random-effects model was conducted.
Main Outcomes and Measures: Outcomes of interest included changes in peak VO2, 6MWD, and Kansas City Cardiomyopathy Questionnaire-12 total symptom score (KCCQ-TSS), clinical summary score (KCCQ-CSS), and overall summary score (KCCQ-OSS).
Results: In this meta-analysis of 17 studies, 23 523 patients (mean [range] age, 69 [60-75] years) were followed over a period ranging from 12 to 52 weeks. Four studies included peak VO2 as an outcome, 7 studies included 6MWD, and 10 studies reported KCCQ scores. Mean (SD) left ventricular ejection fraction was 43.5% (12.4%). Compared with controls, patients receiving SGLT2i treatment experienced significant increases in peak VO2 (mean difference [MD], 1.61 mL/kg/min; 95% CI, 0.59-2.63 mL/kg/min; P = .002) and 6MWD (MD, 13.09 m; 95% CI, 1.20-24.97 m; P = .03). SGLT2i use was associated with increased KCCQ-TSS (MD, 2.28 points; 95% CI, 1.74-2.81 points; P < .001), KCCQ-CSS (MD, 2.14 points; 95% CI, 1.53-2.74 points; P < .001), and KCCQ-OSS (MD, 1.90 points; 95% CI, 1.41-2.39 points; P < .001) scores. Subgroup analysis and meta-regression demonstrated almost all improvements were consistent across ejection fraction, sex, and the presence of diabetes.
Conclusions and Relevance: These findings suggest that in addition to known clinical associations with mortality and hospitalization outcomes, SGLT2i use is associated with improvement in outcomes of interest to patients' everyday lives as measured by objective assessments of maximal exercise capacity and validated QOL questionnaires, regardless of sex or ejection fraction.

DOI: https://doi.org/10.1001/jamanetworkopen.2024.5135
Nature. 2024 Mar 28.

How papers with doctored images can affect scientific reviews.

Sumeet Kulkarni.



Keywords:  Ethics; Publishing

DOI:  https://doi.org/10.1038/d41586-024-00875-2