bims-kimdis 2025-05-11 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–05–11
thirteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Epigenetic regulation by ketone bodies in cardiac diseases and repair.
Intrinsic Ketogenic Capacity of the Heart: Mechanisms and Therapeutic Potential.
Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.
The ketogenic diet and metabolic treatments for neuropsychiatric disorders.
Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.
Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review.
Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.
The central benefit of physiologically induced ketogenic states.
Rationale and design of a randomised phase II multicentre crossover trial investigating a sodium-glucose co-transporter 2 inhibitor, dapagliflozin, combined with a novel continuous ketone monitor in adults with type 1 diabetes to reduce the risk of diabetic ketoacidosis: the PARTNER study.
The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.
Nutritional strategies targeting age-related skeletal muscle fibrosis: underlying mechanisms.
NLRP3 inflammasome: From drug target to drug discovery.
Are Individuals With Type 2 Diabetes Metabolically Inflexible? A Systematic Review and Meta-Analysis.

Can J Physiol Pharmacol. 2025 May 07.

Epigenetic regulation by ketone bodies in cardiac diseases and repair.

Narasimman Gurusamy, Almalki Muteb H Bandar, Sai Katragadda, James Murray, Robert C Speth, Lisa S Robison.

Ketone bodies, particularly β-hydroxybutyrate (BHB), play an important role in the epigenetic regulation of gene expression in cardiac tissues, impacting both cardiac health and disease. This review explores the multifaceted influence of ketone bodies on epigenetic mechanisms, including histone acetylation, DNA methylation, ubiquitination, sirtuins activation, and RNA modulation. By acting as endogenous histone deacetylase inhibitors, ketone bodies enhance histone acetylation, thereby promoting the expression of genes involved in antioxidant defenses, anti-inflammatory responses, and metabolic regulation. Furthermore, BHB affects DNA methylation patterns by altering the availability of key metabolites such as S-adenosylmethionine. Ketogenic diet, which elevates BHB levels, has been shown to modulate gene expression, such as increasing FOXO3a and metallothionein 2, and improve cardiac function. This review highlights the therapeutic potential of ketone bodies in managing cardiac diseases through their epigenetic effects, underscoring the need for further research to elucidate the detailed molecular pathways and long-term impacts of these metabolic interventions.

DOI: https://doi.org/10.1139/cjpp-2024-0270
Circ Res. 2025 May 09. 136(10): 1131-1133

Intrinsic Ketogenic Capacity of the Heart: Mechanisms and Therapeutic Potential.

Rosanna Caputo, Carolina Magdalen Greco.



Keywords:  Editorials; fatty acids; glucose; heart failure; ketone bodies

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326560
J Appl Physiol (1985). 2025 May 08.

Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.

Priyanka Khemraj, Anastasiya Kuznyetsova, David A Hood.

  Skeletal muscle function relies on mitochondria for energy and for mediating its unique adaptive plasticity. The NLRP3 inflammasome complex is an innate immune mechanism that responds to mitochondrial damage-associated molecular patterns (DAMPS), however its activity relative to mitochondrial dysfunction in muscle requires exploration. The purpose of this study was to characterize immune signaling and mitochondrial function in muscle during aging, endurance training, and disuse induced by denervation. Denervation led to decreases in muscle mass, mitochondrial content, and impaired respiration. Protein analyses revealed increases in NF-κB p65 and downstream inflammatory markers including NLRP3, caspase-1, GSDMD-N, STING and IL-1β, along with pro-apoptotic BAX and AIF. When assessing potential DAMPS, denervation led to increased ROS production but no changes in cytosolic mtDNA levels, relative to total mtDNA. Since we hypothesized that inflammasome activation would be increased with age, we studied young (6-8 months) and aged (21-22 months) mice that remained sedentary or underwent a 6-week voluntary running protocol. Aging resulted in marked increases in the expression of multiple pro-inflammatory and pro-apoptotic proteins. Remarkably, training uniformly attenuated age-related increases in BAX, NLRP3, caspase-1, STING, and GSDMD protein expression, and tended to reduce the elevated level of cytosolic mtDNA evident in aged muscle. Training adaptations were evident also in the aged animals by the preservation of muscle mass and improvements in oxygen consumption and endurance performance and were achieved despite a lower training distance than in young animals. Our results strongly implicate endurance training as a promising therapeutic for combatting disuse and age-related inflammation in skeletal muscle.

Keywords:  NLRP3 Inflammasome; exercise; mitochondria; mitochondrial biogenesis; muscle disuse

DOI:  https://doi.org/10.1152/japplphysiol.00038.2025
BJPsych Open. 2025 May 09. 11(3): e94

The ketogenic diet and metabolic treatments for neuropsychiatric disorders.

Christopher M Palmer.

  The ketogenic diet, initially developed for epilepsy treatment, has gained attention as a potential intervention for neuropsychiatric disorders. A groundbreaking study by Campbell et al highlights its feasibility and potential efficacy in bipolar disorder, shedding light on shared mechanisms across neuropsychiatric disorders and the promise of metabolic treatment approaches.

Keywords:  Ketogenic; bipolar; diet; metabolic; neuropsychiatric

DOI:  https://doi.org/10.1192/bjo.2025.50
J Diabetes Investig. 2025 May 07.

Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.

Yoriyasu Suzuki, Tetsuya Amano.

SGLT2 inhibitors increase circulating β-hydroxybutyrate (β-OH-B), a ketone body that may enhance cardiac efficiency in HFrEF. The "thrifty substrate hypothesis" suggests β-OH-B provides more ATP per oxygen consumed than glucose or fatty acids. Clinical studies by Nielsen et al. and Solis-Herrera et al. show that β-OH-B infusion improves cardiac output, ejection fraction, and myocardial blood flow in HFrEF patients-with and without diabetes-without increasing oxygen demand or reducing glucose uptake. These findings support β-OH-B as an additive metabolic fuel, highlighting the therapeutic potential of enhancing cardiac metabolic flexibility.

DOI: https://doi.org/10.1111/jdi.70068
J Sport Health Sci. 2025 May 01. pii: S2095-2546(25)00027-4. [Epub ahead of print] 101049

Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review.

Priyanka Khemraj, Anastasiya Kuznyetsova, David A Hood.

  Skeletal muscle health and function are essential determinants of metabolic health, physical performance, and overall quality of life. The quality of skeletal muscle is heavily dependent on the complex mitochondrial reticulum that contributes toward its unique adaptability. It is now recognized that mitochondrial perturbations can activate various innate immune pathways, such as the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome complex by propagating inflammatory signaling in response to damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is a multimeric protein complex and is a prominent regulator of innate immunity and cell death by mediating the activation of caspase-1, pro-inflammatory cytokines interleukin-1β and interleukin-18 and pro-pyroptotic protein gasdermin-D. While several studies have begun to demonstrate the relationship between various mitochondrial DAMPs (mtDAMPs) and NLRP3 inflammasome activation, the influence of various metabolic states on the production of these DAMPs and subsequent inflammatory profile remains poorly understood. This narrative review aimed to address this by highlighting the effects of skeletal muscle use and disuse on mitochondrial quality mechanisms including mitochondrial biogenesis, fusion, fission and mitophagy. Secondly, this review summarized the impact of alterations in mitochondrial quality control mechanisms following muscle denervation, aging, and exercise training in relation to NLRP3 inflammasome activation. By consolidating the current body of literature, this work aimed to further the understanding of innate immune signaling within skeletal muscle, which can highlight areas for future research and therapeutic strategies to regulate NLRP3 inflammasome activation during divergent metabolic conditions.

Keywords:  Exercise; Innate immune signaling; Mitochondrial quality control; NLRP3 inflammasome; Skeletal muscle disuse

DOI:  https://doi.org/10.1016/j.jshs.2025.101049
J Physiol. 2025 May 05.

Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Christopher G R Perry.

  Reductions in skeletal muscle mitochondrial respiration or increases in mitochondrial reactive oxygen species (ROS) are often interpreted as 'mitochondrial dysfunctions'. However, such changes can also occur as intentional programmed responses to stressors. The term 'mitochondrial dysfunction' could therefore consider the net impact of such responses on other cellular functions. In the case of disuse-induced skeletal muscle atrophy, lower mitochondrial respiration, increased ROS and increased mitochondrial-linked apoptosis have been associated with muscle loss. Such observations support hypotheses that mitochondria contribute to atrophy. If true, there are exciting opportunities for exploring therapeutic strategies that prevent such changes in mitochondrial metabolism. These observations might also support alternative hypotheses where mitochondria are intentionally reprogrammed to serve specific purposes, such as a recalibration of ATP supply to reduced ATP demand during disuse. The goal of this review is to describe what is known regarding skeletal muscle mitochondrial functional responses to muscle disuse, as well as to discuss how these foundational discoveries might lead to new directions that determine whether mitochondrial responses to disuse are causal of atrophy or are adaptive in nature. Three critical questions for consideration include: (1) when is a change in mitochondrial function 'dysfunctional'; (2) how might changes in mitochondrial function represent intentional reprogramming to serve specific purposes; and (3) what factors should be considered when constructing experimental designs to determine the role of mitochondrial functional responses to disuse? Understanding when mitochondrial functional remodelling are dysfunctions or adaptive responses could inform new therapeutic approaches to maintain muscle mass during periods of disuse.

Keywords:  mitochondrial energetics; muscle disuse; skeletal muscle

DOI:  https://doi.org/10.1113/JP284160
J Physiol. 2025 May 05.

The central benefit of physiologically induced ketogenic states.

Antonia Giacco, Giuseppe Petito, Rosalba Senese, Maria Moreno, Assunta Lombardi, Antonia Lanni, Pieter de Lange.

  Ketones not only act as metabolic fuel for the brain in periods of carbohydrate shortage, but also serve as signalling molecules that improve cognition. Ketogenic states can be induced peripherally by physiological interventions such as fasting and exercise, or ketogenic diets/exogenous supplementation. These interventions beneficially act on the brain through partially overlapping peripheral metabolic pathways. We focus on the role of peripheral organs such as the intestine, liver and skeletal muscle in mediating cognitive benefits in response to these interventions and discuss the prominent roles of the nuclear receptor peroxisome proliferator-activated receptor δ, which serves as a nutrient sensor guiding ketones to the brain, where they stimulate the multifunctional cognition-improving factor, brain-derived neurotrophic factor.

Keywords:  BDNF; cognition; exercise; fasting; ketogenic diet; ketones

DOI:  https://doi.org/10.1113/JP287462
BMJ Open. 2025 May 06. 15(5): e098457

Rationale and design of a randomised phase II multicentre crossover trial investigating a sodium-glucose co-transporter 2 inhibitor, dapagliflozin, combined with a novel continuous ketone monitor in adults with type 1 diabetes to reduce the risk of diabetic ketoacidosis: the PARTNER study.

Jennifer Ngan, Yee Wen Kong, Jenna Goad, Michael L H Huang, Alicia Jenkins, Sara Vogrin, Steven Trawley, Adele Manzoney, Miyuki Nakano, Elif Ekinci, Adamandia Kriketos, Spiros Fourlanos, Lynelle Boisseau, Christopher J Nolan, Pamela Taylor, Joanne Fenn, Stephen N Stranks, David Norman O'Neal.

   INTRODUCTION: Sodium-glucose co-transporter inhibitors have potential glycaemic and non-glycaemic benefits in people with type 1 diabetes (T1D). However, the increased risk of diabetic ketoacidosis (DKA) limits their widespread use. We hypothesise that dapagliflozin 10 mg daily, combined with the use of continuous ketone monitoring (CKM) and education strategies to mitigate progression to DKA, will demonstrate improved glycaemic control without increasing DKA events.
METHODS AND ANALYSIS: PARTNER is a multisite 6-month randomised crossover double-masked study involving Australian adults with T1D who have a Haemoglobin A1c (HbA1c) <85.8 mmol/mol (<10%), minimum total daily insulin dose ≥0.4 IU/kg, consume ≥100 g carbohydrates/day and have not had DKA in the last 3 months. All participants will undergo a 2-week run-in period wearing the Abbott FreeStyle Libre 2 Continuous Glucose Monitor (CGM) and Abbott CKM device. Following this, participants are randomised to receive dapagliflozin or placebo for 12 weeks, followed by crossover for a further 12 weeks separated by a 2-week washout period. The primary effectiveness outcome is the Abbott FreeStyle Libre 2 CGM time in range during the final 2 weeks of each stage. The primary safety outcome is the number of episodes of DKA requiring hospitalisation or emergency department presentation. 60 participants will be recruited across five sites.
ETHICS AND DISSEMINATION: The study has received ethical approval from the St Vincent's Hospital Melbourne Human Research Ethics Committee (HREC reference 302/23). The results will be published in peer-reviewed journals and presented at national and international diabetes conferences.
TRIAL REGISTRATION NUMBER: ACTRN12624000448549.

Keywords:  Clinical Protocols; Clinical trials; DIABETES & ENDOCRINOLOGY

DOI:  https://doi.org/10.1136/bmjopen-2024-098457
Physiol Rep. 2025 May;13(9): e70359

The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.

Mauricio Castro Sepulveda, Sylviane Lagarrigue, Francesca Amati.

  Skeletal muscle maximal oxidative capacity (ATPmax) is a key component of age-related sarcopenia and muscle health. The contribution of mitochondrial morphology and electron transport chain supercomplex (SC) assemblies to ATPmax has yet to be determined in human muscle. ATPmax measured in vivo by 31phosphorus magnetic resonance spectroscopy in the quadriceps femoris of nine volunteers (65.5 ± 3.3 years old) was correlated with muscle biopsy outcomes before and after 4 months of supervised exercise. Mitochondrial morphology was assessed in electron micrographs, and SCs were measured by blue native gel electrophoresis. In the sedentary conditions, ATPmax was positively associated with complex (C) I and CIII in SC I+III2+IVn and negatively associated with CI and CIII in SC I+III2. Regarding mitochondrial morphology, ATPmax was positively associated with markers of mitochondrial elongation. Exercise training-induced increases in ATPmax were accompanied by mitochondrial elongation and by the redistribution of free complex III. Indicators of mitochondrial elongation were associated with the redistribution of specific complexes to SC I+III2+IVn. Higher skeletal muscle oxidative capacity in older adults is associated with mitochondrial elongation and the redistribution of electron transport chain complexes into higher rank SCs in the same muscle. Further, we provide evidence that mitochondrial elongation favors mitochondrial SC assembly.

Keywords:  ATPmax; electron transport chain; mitochondrial elongation; respirasome

DOI:  https://doi.org/10.14814/phy2.70359
Crit Rev Food Sci Nutr. 2025 May 08. 1-21

Nutritional strategies targeting age-related skeletal muscle fibrosis: underlying mechanisms.

Iris Cuijpers, Joey Katsburg, Luc J C van Loon, Freddy J Troost, Mireille M J P E Sthijns.

  Aging is associated with a reduced number and function of muscle stem cells (MuSC). This results in a decreased muscle regenerative capacity and increased formation of fibrotic tissue, impairing skeletal muscle function. This review provides an overview of in vitro and in vivo animal studies investigating nutritional interventions with the potential to inhibit pathophysiological mechanisms involved in the development of skeletal muscle fibrosis. Mechanism targets include 1) MuSC function and myogenic differentiation, 2) M1 to M2 macrophage polarization, 3) myofibroblast activity or extracellular matrix (ECM) deposition, and 4) reactive oxygen species (ROS) mediated pathways, such as NOX2/4 activity. Most promising nutrients described in this review are phytonutrients, vitamins and amino acids. Quercetin targets multiple pathways (showing decreased inflammation, ECM expression and NOX2/4 activity) in various cell types and tissues (kidney, aorta, liver and (heart) muscle) of rodents and rabbits, which could contribute to fibrosis development. Additionally, sulforaphane is a promising candidate as it inhibits inflammation, ECM expression, and ROS production in mouse skeletal muscle. After validation of the effects in human skeletal muscle, supplementation with these nutrients could be implemented in a multifaceted intervention (including exercise and adequate protein intake) targeting age-related skeletal muscle fibrosis.

Keywords:  Aging; fibrosis; nutrition; skeletal muscle

DOI:  https://doi.org/10.1080/10408398.2025.2498676
Drug Discov Today. 2025 May 07. pii: S1359-6446(25)00088-1. [Epub ahead of print] 104375

NLRP3 inflammasome: From drug target to drug discovery.

Ling Yin, Hongliang Zhang, Yuhua Shang, Songquan Wu, Tengchuan Jin.

  The immune system employs innate and adaptive immunity to combat pathogens and stress stimuli. Innate immunity rapidly detects pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) via pattern recognition receptors (PRRs), whereas adaptive immunity mediates antigen-specific T/B cell responses. The NLRP3 inflammasome, a key cytoplasmic PRR, consists of leucine-rich repeat, nucleotide-binding, and pyrin domains. Its activation requires priming (signal 1: Toll-like receptors/NOD-like receptors/cytokine receptors) and activation (signal 2: PAMPs/DAMPs/particulates). NLRP3 triggers cytokine storms and neuroinflammation, contributing to inflammatory diseases. Emerging therapies target NLRP3 via nuclear receptors (transcriptional regulation), adeno-associated virus (AAV) vectors (gene delivery), and microRNAs (post-transcriptional modulation). This review highlights NLRP3's signaling cascade, pathological roles, and combinatorial treatments leveraging nuclear receptors, AAVs, and microRNAs for immunomodulation.

Keywords:  AAV; NLRP3 inflammasome; drug discovery; drug target; miRNA; nuclear receptor

DOI:  https://doi.org/10.1016/j.drudis.2025.104375
Endocrinol Diabetes Metab. 2025 May;8(3): e70044

Are Individuals With Type 2 Diabetes Metabolically Inflexible? A Systematic Review and Meta-Analysis.

Maria Hansen, Kristine Kjær Lange, Martin Bjørn Stausholm, Flemming Dela.

   AIM: Type 2 diabetes (T2D) is characterised by insulin resistance and possibly by impaired metabolic flexibility, the latter referring to the body's ability to switch between fuel sources. This review systematically examines metabolic flexibility, measured by changes in the respiratory exchange ratio (ΔRER) during hyperinsulinaemic clamps, across lean, overweight/obese, and T2D populations.
METHODS: A comprehensive search of PubMed identified 65 studies meeting the inclusion criteria, with 35 using a ~40 mU/m2/min insulin infusion rate for accurate comparisons. These studies included 985 participants: 256 lean, 497 overweight/obese, and 232 T2D individuals. The differences in ΔRER between the three groups were meta-analysed.
RESULTS: Basal RER values did not significantly differ across groups, but insulin-stimulated ΔRER was higher in lean individuals compared to overweight/obese and T2D groups (ΔRER values 0.10, 0.07 and 0.07, respectively; p = 0.037) indicating greater metabolic flexibility in the lean group. However, high statistical heterogeneity in the ΔRER within-group results (I2 values: 92.3%-94.5%) suggests considerable variability among studies. A meta-regression analysis accounting for age, sex, and BMI indicated that only BMI was significantly associated with ΔRER. Factors contributing to the remaining heterogeneity likely include differences in participant characteristics (e.g., glycaemic control) and study design.
CONCLUSIONS: The review highlights the need for standardised data presentation in metabolic studies. Overall, metabolic flexibility appears more influenced by overweight status than T2D per se, challenging the notion of a distinct metabolic inflexibility threshold for T2D.

Keywords:  hyperinsulinemic clamp; metabolic flexibility; type 2 diabetes

DOI:  https://doi.org/10.1002/edm2.70044