bims-kimdis 2025-01-19 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–01–19
27 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Effect of exogenous β-hydroxybutyrate on BDNF signalling, cognition, and amyloid precursor protein processing in humans with T2D and insulin resistant rodents.
A Single Night in Hypoxia Either with or without Ketone Ester Ingestion Reduces Sleep Quality Without Impacting Next Day Exercise Performance.
Carbohydrate supplementation maintains physical performance during short-term energy deficit despite reductions in exogenous glucose oxidation.
Ketone monoester ingestion improves cardiac function in adults with type 2 diabetes: a double-blind, placebo controlled, randomised, crossover trial.
Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise.
Primary Roles of Branched Chain Amino Acids (BCAAs) and Their Metabolism in Physiology and Metabolic Disorders.
β-Hydroxybutyrate Alleviates Atherosclerotic Calcification by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis via AMPK/Nrf2 Pathway.
Very low-calorie ketogenic diet reduces central blood pressure and cardiometabolic risk in post-menopausal women with essential hypertension and obesity: a single-center, prospective, open-label, clinical study.
Mechanisms of Skeletal Muscle Dysfunction in Cardiometabolic HFpEF and Its Reversal With Exercise Training.
Critical molecular outcomes of time-restricted feeding during ageing: a look beyond body composition.
Revealing the dance of NLRP3: spatiotemporal patterns in inflammasome activation.
Effects of 24-Hour Diet- or Exercise-Induced Energy Availability Manipulations on Substrate Utilization and Performance.
Exercise Therapy Rescues Skeletal Muscle Dysfunction and Exercise Intolerance in Cardiometabolic HFpEF.
DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.
Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing.
Reacting to reductive stress at the mitochondrial import gate.
Ratio of Skeletal Muscle Mass to Visceral Fat Area Is a Useful Marker for Assessing Left Ventricular Diastolic Dysfunction among Koreans with Preserved Ejection Fraction: An Analysis of the Random Forest Model.
Interaction and regulation of the mitochondrial proteome - in health and disease.
Effects of time-restricted eating with exercise on body composition in adults: a systematic review and meta-analysis.
Representing Structural Isomer Effects in a Coarse-Grain Model of Poly(Ether Ketone Ketone).
Mitochondrial Complex I and ROS control synapse function through opposing pre- and postsynaptic mechanisms.
Effects of leg immobilization and recovery resistance training on skeletal muscle-molecular markers in previously resistance trained versus untrained adults.
Mitochondria and NLRP3: To die or inflame.
Changes in Muscle Quality Following Short-Term Resistance Training in Older Adults: A Comparison of Echo Intensity and Texture Analysis.
Obesity as an influencing factor for the occurrence of caffeine-induced effects in women.
Protocol for the three-dimensional analysis of rodent skeletal muscle.
Role of PI3 Kinases in Cell Signaling and Soleus Muscle Atrophy During Three Days of Unloading.

Am J Physiol Cell Physiol. 2025 Jan 13.

Effect of exogenous β-hydroxybutyrate on BDNF signalling, cognition, and amyloid precursor protein processing in humans with T2D and insulin resistant rodents.

B J Baranowski, B F Oliveira, K Falkenhain, J P Little, A Mohammad, S Beaudette, M S Finch, H G Caldwell, H Neudorf, R E K MacPherson, Jeremy J Walsh.

  Introduction People with type 2 diabetes (T2D) have a greater risk of developing neurodegenerative diseases, like Alzheimer's disease, in later life. Exogenous ketone supplements containing the ketone body β-hydroxybutyrate (β-OHB) may be a strategy to protect the brain as β-OHB can support cerebral metabolism and promote neuronal plasticity via expression of brain-derived neurotrophic factor (BDNF). Methods and Results Parallel human (ClinicalTrials.gov ID NCT04194450, ClinicalTrials.gov ID NCT05155410) and rodent trials were conducted to characterize the effect of acute and short-term exogenous ketone supplementation on indices of brain health. First, we aimed to investigate the effect of acute and short-term supplementation of exogenous ketone monoester on circulating BDNF and cognition in adults with T2D. There were no effects of ketone supplementation on plasma BDNF or cognition. Second, we aimed to investigate the mechanistic effects of acute and chronic β-OHB supplementation on cortical BDNF content and recognition memory in C57BL/6J mice with and without insulin resistance. Acutely, β-OHB did not alter recognition memory or BDNF content. Similarly, chronic β-OHB supplementation did not alter recognition memory or BDNF content. Conclusions Collectively, our data demonstrates that ketone supplementation does not elevate BDNF content in humans or mice. Further, our data does not support the involvement of BDNF in the potential cognitive benefits of β-OHB supplementation.

Keywords:  Alzheimer's disease; BACE1; BDNF; Cognitive function; Insulin resistance; type 2 diabetes; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00867.2024
Med Sci Sports Exerc. 2024 Nov 18.

A Single Night in Hypoxia Either with or without Ketone Ester Ingestion Reduces Sleep Quality Without Impacting Next Day Exercise Performance.

Myrthe Stalmans, Domen Tominec, Ruben Robberechts, Wout Lauriks, Monique Ramaekers, Tadej Debevec, Chiel Poffé.

BACKGROUND: Sleeping at altitude is highly common in athletes as an integral part of altitude training camps or sport competitions. However, concerns have been raised due to expected negative effects on sleep quality, thereby potentially hampering exercise recovery and next-day exercise performance. We recently showed that ketone ester (KE) ingestion beneficially impacted sleep following strenuous, late evening exercise in normoxia, and alleviated hypoxemia. Therefore, we hypothesized that KE ingestion may be an effective strategy to attenuate hypox(em)ia-induced sleep dysregulations.
METHODS: Eleven healthy, male participants completed three experimental sessions including normoxic training and subsequent sleep in normoxia or at a simulated altitude of 3,000 m while receiving either KE or placebo post-exercise and pre-sleep. Sleep was evaluated using polysomnography, while next-day exercise performance was assessed through a 30-min all-out time trial (TT30'). Physiological measurements included oxygen status, heart rate variability, ventilatory parameters, blood acid-base balance and capillary blood gases.
RESULTS: Hypoxia caused a ~3% drop in sleep efficiency, established through a doubled wakefulness after sleep onset and a ~22% reduction in slow wave sleep. KE ingestion alleviated the gradual drop in SpO2 throughout the first part of the night, but did not alter hypoxia-induced sleep dysregulations. Neither KE, nor nocturnal hypoxia affected TT30' performance, but nocturnal hypoxia hampered heart rate recovery following TT30'.
CONCLUSIONS: We observed that sleeping at 3,000 m altitude impairs sleep efficiency. Although this hypoxia-induced sleep disruption was too subtle to limit exercise performance, we for the first time indicate that sleeping at altitude might impair next-day exercise recovery. KE alleviated nocturnal hypoxemia only when SpO2 values dropped below ~85%, but this did not translate into improved sleep or next-day exercise performance.

DOI: https://doi.org/10.1249/MSS.0000000000003604
Am J Physiol Endocrinol Metab. 2025 Jan 15.

Carbohydrate supplementation maintains physical performance during short-term energy deficit despite reductions in exogenous glucose oxidation.

Lee M Margolis, Jillian T Allen, Nancy E Murphy, Christopher T Carrigan, Emily E Howard, David E Barney, Devin J Drummer, Julia Michalak, Arny A Ferrando, Stefan M Pasiakos, Jess A Gwin.

  Exogenous glucose oxidation is reduced 55% during aerobic exercise after three days of complete starvation. Whether energy deficits more commonly experienced by athletes and military personnel similarly affect exogenous glucose oxidation and what impact this has on physical performance remains undetermined. This randomized, longitudinal parallel study aimed to assess the effects of varying magnitudes of energy deficit (DEF) on exogenous glucoseoxidation and physical performance compared to energy balance (BAL). Participants consumed a4-day BAL diet, followed by a 6-day 20% (n=10), 40% (n=10), or 60% (n=10) DEF diet. At the end of each energy phase participants performed 90-min of steady-state cycle ergometry (56±3% V̇O2peak) while consuming a glucose drink (80 g), followed by a time to exhaustion (TTE) performance test. Substrate oxidation (g/min) was determined by indirect calorimetry and 13C glucose. Muscle glycogen (mmol/kg dry weight) and transcript accumulation were assessed in rested fasted muscle collected before exercise in each phase. Muscle glycogen was lower (P = 0.002) during DEF (365±179) than BAL (456±125), regardless of group. Transcriptional regulation of glucose uptake (GLUT4italic> and IRS2) and glycogenolysis (HKII and PKM) were lower (P < 0.05) during DEF than BAL, independent of group. Regardless of group, exogenous glucose oxidation was 10% lower (P < 0.001) during DEF (0.38±0.08) than BAL (0.42±0.08). There was no evidence of a difference in TTE between BAL and DEF or between groups. In conclusion, despite modest reduction in exogenous glucose oxidative capacity during energy deficit, physical performance was similar compared with balance.

Keywords:  endurance exercise; military; physical activity; substrate metabolism

DOI:  https://doi.org/10.1152/ajpendo.00418.2024
J Appl Physiol (1985). 2025 Jan 17.

Ketone monoester ingestion improves cardiac function in adults with type 2 diabetes: a double-blind, placebo controlled, randomised, crossover trial.

M Perissiou, Z L Saynor, K Feka, C Edwards, T J James, J Corbett, H Mayes, J Shute, M Cummings, M I Black, W D Strain, J P Little, A I Shepherd.

  Type 2 diabetes (T2D) is a metabolic disease associated with cardiovascular dysfunction. The myocardium preferentially uses ketones over free fatty acids as a more energy efficient substrate. The primary aim was to assess the effects of ketone monoester (Kme) ingestion on cardiac output index (Q̇i). Secondary aims were to assess the effects of Kme ingestion on markers of cardiac haemodynamics, muscle oxygenation and vascular function at rest, during and following step-incremental cycling. We undertook a double-blind, randomised, crossover design study in 13 adults (age, 66±10 y; BMI, 31.3±7.0 kg·m-2) with T2D. Participants completed two conditions, where they ingested a Kme (0.115 g‧kg-1) or a placebo taste-mathced drink. Cardiac function was measured using thoracic impedance cardiography and muscle oxygenation of the calf was determined via near-infrared spectroscopy. Macrovascular endothelial function was measured by flow mediated dilation (FMD) and microvascular endothelial function was measured via transdermal delivery of acetylcholine (ACh) and insulin. Circulating β-hydroxybutyrate [β-Hb] was measured throughout. Kme ingestion raised circulating β-Hb throughout the protocol (peak 1.9 mM; P=0.001 vs. placebo). Kme ingestion increased Q̇i by 0.75±0.5 L∙min-1∙m-2 (P=0.003) stroke volume index by 7.2±4.5 mL∙m-2 (P=0.001), and peripheral muscle oxygenation by 9.9±7.1% (P=0.001) and reduced systemic vascular resistance index by-420±-225 dyn∙s-1∙cm-5∙m-2 (P=0.031) compared to placebo condition. There were no differences between Kme and placebo in heart rate (P=0.995), FMD (P=0.542), ACh max (P=0.800), insulin max (P=0.242). Ingestion of Kme improved Q̇i, stroke volume index and peripheral muscle oxygenation, but did not alter macro- or microvascular endothelial function in people with T2D.

Keywords:  cardiovascular haemodynamics; diabetes; exercise; ketosis; muscle oxygenation; near-infrared spectroscopy; thoracic impedance cardiography; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/japplphysiol.00800.2024
J Physiol. 2025 Jan 14.

Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise.

Taylor J Kelty, Nathan R Kerr, Chih H Chou, Grace E Shryack, Christopher L Taylor, Alexa A Krause, Alexandra R Knutson, Josh Bunten, Tom E Childs, Grace M Meers, Ryan J Dashek, Patrycja Puchalska, Peter A Crawford, John P Thyfault, Frank W Booth, R Scott Rector.

  Extensive research has demonstrated endurance exercise to be neuroprotective. Whether these neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. To investigate the role of hepatic ketone production on brain health during exercise, healthy 6-month-old female rats underwent viral knockdown of the rate-limiting enzyme in the liver that catalyses the first reaction in ketogenesis: 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2). Rats were then subjected to either a bout of acute exercise or 4 weeks of chronic treadmill running (5 days/week) and cognitive behavioural testing. Acute exercise elevated ketone plasma concentration 1 h following exercise. Hepatic HMGCS2 knockdown, verified by protein expression, reduced ketone plasma concentration 1 h after acute exercise and 48 h after chronic exercise. Proteomic analysis and enrichment of the frontal cortex revealed hepatic HMGCS2 knockdown reduced markers of mitochondrial function 1 h after acute exercise. HMGCS2 knockdown significantly reduced state 3 complex I + II respiration in isolated mitochondria from the frontal cortex after chronic exercise. Spatial memory and protein markers of synaptic plasticity were significantly reduced by HMGCS2 knockdown. These deficiencies were prevented by chronic endurance exercise training. In summary, these are the first data to propose that hepatic ketogenesis is required to maintain cognition and mitochondrial function, irrespective of training status, and that endurance exercise can overcome neuropathology caused by insufficient hepatic ketogenesis. These results establish a mechanistic link between liver and brain health that enhance our understanding of how peripheral tissue metabolism influences brain health. KEY POINTS: Decades of literature demonstrate endurance exercise to be neuroprotective. Whether neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. This study provides the first set of data that suggest hepatic ketogenesis is required to maintain cognition, synaptic plasticity and mitochondrial function. These data indicate endurance exercise can protect against cognitive decline caused by compromised hepatic ketogenesis. These results establish a mechanistic link between liver and brain function, prompting further investigation of how hepatic metabolism influences brain health.

Keywords:  HMGCS2; cerebral cortex; cognitio; exercise; ketogenesis; liver; mitochondria; proteomics

DOI:  https://doi.org/10.1113/JP287573
Molecules. 2024 Dec 27. pii: 56. [Epub ahead of print]30(1):

Primary Roles of Branched Chain Amino Acids (BCAAs) and Their Metabolism in Physiology and Metabolic Disorders.

Tomoki Bo, Junichi Fujii.

  Leucine, isoleucine, and valine are collectively known as branched chain amino acids (BCAAs) and are often discussed in the same physiological and pathological situations. The two consecutive initial reactions of BCAA catabolism are catalyzed by the common enzymes referred to as branched chain aminotransferase (BCAT) and branched chain α-keto acid dehydrogenase (BCKDH). BCAT transfers the amino group of BCAAs to 2-ketoglutarate, which results in corresponding branched chain 2-keto acids (BCKAs) and glutamate. BCKDH performs an oxidative decarboxylation of BCKAs, which produces their coenzyme A-conjugates and NADH. BCAT2 in skeletal muscle dominantly catalyzes the transamination of BCAAs. Low BCAT activity in the liver reduces the metabolization of BCAAs, but the abundant presence of BCKDH promotes the metabolism of muscle-derived BCKAs, which leads to the production of glucose and ketone bodies. While mutations in the genes responsible for BCAA catabolism are involved in rare inherited disorders, an aberrant regulation of their enzymatic activities is associated with major metabolic disorders such as diabetes, cardiovascular disease, and cancer. Therefore, an understanding of the regulatory process of metabolic enzymes, as well as the functions of the BCAAs and their metabolites, make a significant contribution to our health.

Keywords:  branched chain aminotransferase; branched chain α-keto acid dehydrogenase; cancer; diabetes; gluconeogenesis; ketogenesis

DOI:  https://doi.org/10.3390/molecules30010056
Nutrients. 2024 Dec 30. pii: 111. [Epub ahead of print]17(1):

β-Hydroxybutyrate Alleviates Atherosclerotic Calcification by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis via AMPK/Nrf2 Pathway.

Yu Chen, Yiran You, Xin Wang, Yufeng Jin, Yupeng Zeng, Zhijun Pan, Dan Li, Wenhua Ling.

   BACKGROUND: Atherosclerotic calcification (AC) is a common feature of atherosclerotic cardiovascular disease. β-Hydroxybutyrate (BHB) has been identified as a molecule that influences cardiovascular disease. However, whether BHB can influence AC is still unknown.
METHODS AND RESULTS: In this study, ApoE-/- mice, fed a Western diet, were used to examine the effects of BHB on AC. Rat vascular smooth muscle cells (VSMCs) were used to verify the impacts of BHB on AC and to explore the underlying mechanisms. The results show that Western diet-challenged ApoE-/- mice, supplemented with BHB for 24 weeks, exhibited reduced calcified areas, calcium content, and alkaline phosphatase (ALP) activity in the aortas, as well as ameliorated severity of AC. Furthermore, BHB downregulated the expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), thereby reducing endoplasmic reticulum stress (ERS) and ERS-mediated apoptosis in the aortas of the mice. Consistently, in vitro studies showed that BHB reduced ALP activity and calcium content in VSMCs, and inhibited VSMC calcification. Additionally, BHB suppressed ERS-mediated apoptosis in VSMCs.
CONCLUSIONS: In summary, the present results demonstrate that BHB can alleviate atherosclerotic calcification by inhibiting ERS-mediated apoptosis. Therefore, BHB may serve as a viable therapeutic agent for AC.

Keywords:  apoptosis; atherosclerotic calcification; endoplasmic reticulum stress; β-Hydroxybutyrate

DOI:  https://doi.org/10.3390/nu17010111
Nutr Metab Cardiovasc Dis. 2024 Dec 20. pii: S0939-4753(24)00472-1. [Epub ahead of print] 103838

Very low-calorie ketogenic diet reduces central blood pressure and cardiometabolic risk in post-menopausal women with essential hypertension and obesity: a single-center, prospective, open-label, clinical study.

Barbara Pala, Laura Pennazzi, Giulia Nardoianni, Speranza D Rubattu, Massimo Volpe, Anna Maria Colao, Emanuele Barbato, Giuliano Tocci.

   BACKGROUND AND AIMS: Obesity represents a crucial modifiable risk factor for cardiovascular complications. Two dietary approaches, Very Low-Calorie Ketogenic (VLCKD) and Intermittent Fasting (IFD) diets, have demonstrated to reduce blood pressure (BP) and produce cardiovascular and metabolic advantages. We aimed to evaluate the effects of VLCKD or IFD compared to Free Diet (FD) on office brachial and central systolic BP levels. Secondary outcomes included changes from baseline of diastolic BP and several weight-related indexes.
METHODS AND RESULTS: In this single-center, open-label, prospective clinical study, post-menopausal women with treated uncomplicated hypertension and obesity were assigned to 3 dietary programs: VLCKD, IF, and FD. All patients underwent BP measurements, dietary consultation with personalized dietary program, and blood tests for metabolic parameters. All outcome variables were measured at baseline (T0), two (T1) and six months (T2). We included 18 patients in the VLCKD, 16 in the IFD and 9 in the FD groups, respectively. At T2 VLCKD patients showed significantly lower brachial systolic (p = 0.005) and diastolic (p = 0.038), central systolic (p = 0.02) and diastolic (p = 0.03) BP levels than those in other groups. VLCKD also induced reductions in weight (p = 0.03), WC (p < 0.01), WHR (p < 0.01), BFP (p < 0.01); TOT-C (p = 0.01), LDL-C (p < 0.01), and triglycerides (p = 0.02). No relevant changes were observed in IF and FD groups.
CONCLUSIONS: KD emerged as the clear front-runner in reducing brachial and central office systolic/diastolic BP levels and weight-related parameters in post-menopausal women with treated hypertension and obesity.

Keywords:  Central blood pressure; High blood pressure; Hypertension; Intermittent fasting diet; Menopause; Obesity; Very low-calorie ketogenic diet; Women

DOI:  https://doi.org/10.1016/j.numecd.2024.103838
JACC Basic Transl Sci. 2024 Dec;9(12): 1426-1428

Mechanisms of Skeletal Muscle Dysfunction in Cardiometabolic HFpEF and Its Reversal With Exercise Training.

Bharathi Upadhya, Dalane W Kitzman.



Keywords:  branched-chained amino acids; exercise; heart failure with preserved ejection fraction; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.jacbts.2024.10.009
J Physiol. 2025 Jan 12.

Critical molecular outcomes of time-restricted feeding during ageing: a look beyond body composition.

Mariana Lima Ribeiro, Izabela Monteiro de Araújo, Ana Paula Morelli.



Keywords:  ageing; dietary intervention; time‐restricted feeding

DOI:  https://doi.org/10.1113/JP287927
Immunometabolism (Cobham). 2025 Jan;7(1): e00053

Revealing the dance of NLRP3: spatiotemporal patterns in inflammasome activation.

Lauren Spector, Naeha Subramanian.

  The nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing-protein 3 (NLRP3) inflammasome is a multiprotein complex that plays a critical role in the innate immune response to both infections and sterile stressors. Dysregulated NLRP3 activation has been implicated in a variety of autoimmune and inflammatory diseases, including cryopyrin-associated periodic fever syndromes, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, and cancer. Consequently, fine-tuning NLRP3 activity holds significant therapeutic potential. Studies have implicated several organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), the Golgi apparatus, endosomes, and the centrosome, in NLRP3 localization and inflammasome assembly. However, reports of conflict and many factors regulating interactions between NLRP3 and subcellular organelles remain unknown. This review synthesizes the current understanding of NLRP3 spatiotemporal dynamics, focusing on recent literature that elucidates the roles of subcellular localization and organelle stress in NLRP3 signaling and its crosstalk with other innate immune pathways converging at these organelles.

Keywords:  NLRP3; inflammasome; innate immunity; organelle; subcellular

DOI:  https://doi.org/10.1097/IN9.0000000000000053
Med Sci Sports Exerc. 2024 Nov 22.

Effects of 24-Hour Diet- or Exercise-Induced Energy Availability Manipulations on Substrate Utilization and Performance.

Ella S Smith, Megan Kuikman, Jonathon Weakley, Nicolin Tee, Rachel McCormick, Kathryn E Ackerman, Kirsty J Elliott-Sale, Trent Stellingwerff, Rachel Harris, Alannah K A McKay, Louise M Burke.

PURPOSE: To examine sex-based differences in substrate oxidation, postprandial metabolism, and performance in response to 24-hour manipulations in energy availability (EA), induced by manipulations to energy intake (EI) or exercise energy expenditure (EEE).
METHODS: In a Latin Square design, 20 endurance athletes (10 females using monophasic oral contraceptives and 10 males) undertook five trials, each comprising three consecutive days. Day one was a standardized period of high EA; EA was then manipulated on day two; post-intervention testing occurred on day three. Day two EA was low/high/higher EA (LEA/HEA/GEA) at 15/45/75 kcal·kg-1FFM·day-1, with conditions of LEA and HEA separately achieved by manipulations of either EI or EEE (LEA REST/EX vs. HEAREST/EX). On day three, fasted peak fat oxidation during cycling and two-hour postprandial (high carbohydrate and energy meal) metabolism were assessed, alongside several performance tests: Wingate, countermovement jump (CMJ), squat jump (SJ), isometric mid-thigh pull (IMTP), and the Stroop Color and Word Test.
RESULTS: Highest peak fat oxidation occurred under LEA induced by exercise (p < 0.01), with no difference between sexes. Postprandial glucose (p < 0.01) and insulin (p < 0.05) responses were highest across both sexes when LEA was induced by diet. Relative peak and mean power throughout the Wingate, alongside CMJ height did not differ between EA conditions (p > 0.05), while SJ height was lower during GEA than both LEAREST (p = 0.045) and HEAEX (p = 0.016). IMTP peak force and the Stroop effect did not change with altered EA (p > 0.05).
CONCLUSIONS: Acute (24-hour) exercise-induced LEA influenced fasted substrate oxidation more than diet-induced LEA, while 24 hours of LEA did not impair strength/power, sprint capacity, or cognitive performance. Finally, the responses to EA manipulations did not differ between sexes.

DOI: https://doi.org/10.1249/MSS.0000000000003608
JACC Basic Transl Sci. 2024 Dec;9(12): 1409-1425

Exercise Therapy Rescues Skeletal Muscle Dysfunction and Exercise Intolerance in Cardiometabolic HFpEF.

Heather Quiriarte, Robert C Noland, James E Stampley, Gregory Davis, Zhen Li, Eunhan Cho, Youyoung Kim, Jake Doiron, Guillaume Spielmann, Sujoy Ghosh, Sanjiv J Shah, Brian A Irving, David J Lefer, Timothy D Allerton.

  Exercise intolerance, a hallmark of heart failure with preserved ejection fraction (HFpEF) exacerbated by obesity, involves unclear mechanisms related to skeletal muscle metabolism. In a "2-hit" model of HFpEF, we investigated the ability of exercise therapy (voluntary wheel running) to reverse skeletal muscle dysfunction and exercise intolerance. Using state-of-the-art metabolic cages and a multiomic approach, we demonstrate exercise can rescue dysfunctional skeletal muscle lipid and branched-chain amino acid oxidation and restore exercise capacity in mice with cardiometabolic HFpEF. These results underscore the importance of skeletal muscle metabolism to improve exercise intolerance in HFpEF.

Keywords:  branched-chained amino acids; exercise; heart failure with preserved ejection fraction; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.jacbts.2024.07.009
Nutrients. 2024 Dec 31. pii: 149. [Epub ahead of print]17(1):

DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.

Valentina Gentili, Giovanna Schiuma, Latha Nagamani Dilliraj, Silvia Beltrami, Sabrina Rizzo, Djidjell Lara, Pier Paolo Giovannini, Matteo Marti, Daria Bortolotti, Claudio Trapella, Marco Narducci, Roberta Rizzo.

   BACKGROUND: A neuroinflammatory disease such as Alzheimer's disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways.
METHODS: We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound's effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates.
RESULTS: DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation.
CONCLUSIONS: In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression.

Keywords:  Alzheimer’s disease; DAG-MAG-ΒHB; blood–brain barrier; exogenous ketones; ketone diester; neuroprotection; therapeutic ketosis

DOI:  https://doi.org/10.3390/nu17010149
BMC Genomics. 2025 Jan 13. 26(1): 29

Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing.

Gulam Altab, Brian J Merry, Charles W Beckett, Priyanka Raina, Inês Lopes, Katarzyna Goljanek-Whysall, João Pedro de Magalhães.

  Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. Hub genes implicated in both ageing and CR included Gc, Plg, Irf7, Ifit3, Usp18, Rsad2, Blm and RT1-A2, whilst those exclusively implicated in CR responses included Alb, Apoa1, Ambp, F2, Apoh, Orm1, Mx1, Oasl2 and Rtp4. Hub genes involved in ageing but unaffected by CR included Fgg, Fga, Fgb and Serpinc1. In conclusion, this comprehensive RNA sequencing study highlights gene expression patterns, hub genes and signalling pathways most affected by ageing in skeletal muscle. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.

Keywords:  Diet; Functional genomics; Nutrigenomics; Sarcopenia

DOI:  https://doi.org/10.1186/s12864-024-11051-1
Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]

Reacting to reductive stress at the mitochondrial import gate.

Sylvie Callegari.

  A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.

Keywords:  TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2024.12.013
J Obes Metab Syndr. 2025 Jan 14.

Ratio of Skeletal Muscle Mass to Visceral Fat Area Is a Useful Marker for Assessing Left Ventricular Diastolic Dysfunction among Koreans with Preserved Ejection Fraction: An Analysis of the Random Forest Model.

Jin Kyung Oh, Yuri Seo, Wonmook Hwang, Sami Lee, Yong-Hoon Yoon, Kyupil Kim, Hyun Woong Park, Jae-Hyung Roh, Jae-Hwan Lee, Minsu Kim.

   Background: Although the presence of both obesity and reduced muscle mass presents a dual metabolic burden and additively has a negative effect on a variety of cardiometabolic parameters, data regarding the associations between their combined effects and left ventricular diastolic function are limited. This study investigated the association between the ratio of skeletal muscle mass to visceral fat area (SVR) and left ventricular diastolic dysfunction (LVDD) in patients with preserved ejection fraction using random forest machine learning.
Methods: In total, 1,070 participants with preserved left ventricular ejection fractions who underwent comprehensive health examinations, including transthoracic echocardiography and bioimpedance body composition analysis, were enrolled. SVR was calculated as an index of sarcopenic obesity by dividing the appendicular skeletal muscle mass by the visceral fat area.
Results: In the random forest model, age and SVR were the most powerful predictors of LVDD. Multivariate logistic regression analysis demonstrated that older age (adjusted odds ratio [OR], 1.11; 95% confidence interval [CI], 1.07 to 1.15) and lower SVR (adjusted OR, 0.08; 95% CI, 0.01 to 0.57) were independent risk factors for LVDD. SVR showed a significant improvement in predictive performance and fair predictability for LVDD, with the highest area under the curve noted in both men and women, with statistical significance. In non-obese and metabolically healthy individuals, the lowest SVR tertile was associated with a greater risk of LVDD compared to the highest SVR tertile.
Conclusion: Decreased muscle mass and increased visceral fat were significantly associated with LVDD compared to obesity, body fat composition, and body muscle composition indices.

Keywords:  Bioelectrical impedance measurement; Left ventricular diastolic dysfunction; Skeletal muscle mass-to-visceral fat area ratio

DOI:  https://doi.org/10.7570/jomes24027
Expert Rev Proteomics. 2025 Jan 15. 1-15

Interaction and regulation of the mitochondrial proteome - in health and disease.

Johan Palmfeldt.

   INTRODUCTION: Mitochondria contain multiple pathways including energy metabolism and several signaling and synthetic pathways. Mitochondrial proteomics is highly valuable for studying diseases including inherited metabolic disorders, complex and common disorders like neurodegeneration, diabetes, and cancer, since they all to some degree have mitochondrial underpinnings.
AREAS COVERED: The main mitochondrial functions and pathways are outlined, and systematic protein lists are presented. The main energy metabolic pathways are as follows: iron-sulfur cluster synthesis, one carbon metabolism, catabolism of hydrogen sulfide, kynurenines and reactive oxygen species (ROS), and others, described with the aim of laying a foundation for systematic mitochondrial pathway analysis based on proteomics data. The links of the proteins and pathways to functional effects and diseases are discussed. The disease examples are focussed on inherited metabolic disorders, cancer, neurological, and cardiovascular disorders.
EXPERT OPINION: To elucidate the role of mitochondria in health and disease, there is a need for comprehensive proteomics analyses with stringent, systematic data treatment for proper interpretation of mitochondrial pathway data. In that way, comprehensive hypothesis-based research can be performed based on proteomics data.

Keywords:  Mitochondrion; NAD; biomarker panels; kynurenine; metabolic disorders; oxidative phosphorylation; proteomics; stress response

DOI:  https://doi.org/10.1080/14789450.2025.2451704
Int J Obes (Lond). 2025 Jan 10.

Effects of time-restricted eating with exercise on body composition in adults: a systematic review and meta-analysis.

Harry M Hays, Pouria Sefidmooye Azar, Minsoo Kang, Grant M Tinsley, Nadeeja N Wijayatunga.

BACKGROUND: The effects of time-restricted eating (TRE) with exercise on body composition in adults are not clear.
OBJECTIVE: This meta-analysis aimed to assess the effects of TRE when followed in combination with various forms of exercise, including aerobic, resistance, and combined aerobic and resistance [concurrent] training on body composition.
METHODS: Studies published up to May 2023 were searched in EBSCOhost (MEDLINE, CINAHL, SPORTSDISCUS), PubMed, and SCOPUS databases. Fifteen studies, including 338 participants, that evaluated TRE vs. unrestricted eating in individuals performing exercise were analyzed. A random-effects model was used to calculate the weighted mean effect sizes (ES) with 95% confidence intervals (95% CI's).
RESULTS: According to the pooled results, TRE had a small but significant reduction of fat mass (FM) kg with an effect size of -0.20 (95% CI = -0.28 to -0.13, p < 0.001) and on body fat percent (BF%) with an effect size of -0.23 (95% CI = -0.35 to -0.11, p < 0.001). The prediction interval ranged from -0.48 to 0.08 for FM and from -0.64 to 0.18 for BF%, respectively. TRE did not significantly alter fat-free mass (FFM) kg compared to control (p = 0.07). Furthermore, age, body mass index (BMI), exercise type, study duration, and energy intake did not have a significant impact on the variation in effect sizes according to the subgroup analyses (p > 0.05).
CONCLUSION: TRE with exercise may reduce fat mass compared to an unrestricted eating window exercise-matched control while preserving FFM. However, more studies are needed.

DOI: https://doi.org/10.1038/s41366-024-01704-2
Polymers (Basel). 2025 Jan 05. pii: 117. [Epub ahead of print]17(1):

Representing Structural Isomer Effects in a Coarse-Grain Model of Poly(Ether Ketone Ketone).

Chris D Jones, Jenny W Fothergill, Rainier Barrett, Lina N Ghanbari, Nicholas R Enos, Olivia McNair, Jeffrey Wiggins, Eric Jankowski.

  Carbon-fiber composites with thermoplastic matrices offer many processing and performance benefits in aerospace applications, but the long relaxation times of polymers make it difficult to predict how the structure of the matrix depends on its chemistry and how it was processed. Coarse-grained models of polymers can enable access to these long-time dynamics, but can have limited applicability outside the systems and state points that they are validated against. Here we develop and validate a minimal coarse-grained model of the aerospace thermoplastic poly(etherketoneketone) (PEKK). We use multistate iterative Boltzmann inversion to learn potentials with transferability across thermodynamic states relevant to PEKK processing. We introduce tabulated EKK angle potentials to represent the ratio of terephthalic (T) and isophthalic (I) acid precursor amounts, and validate against rheological experiments: The glass transition temperature is independent to T/I, but chain relaxation and melting temperature is. In sum we demonstrate a simple, validated model of PEKK that offers 15× performance speedups over united atom representations that enables studying thermoplastic processing-structure-property-performance relationships.

Keywords:  coarse-graining; molecular dynamics; thermoplastic

DOI:  https://doi.org/10.3390/polym17010117
bioRxiv. 2024 Dec 31. pii: 2024.12.30.630694. [Epub ahead of print]

Mitochondrial Complex I and ROS control synapse function through opposing pre- and postsynaptic mechanisms.

Bhagaban Mallik, C Andrew Frank.

  Neurons require high amounts energy, and mitochondria help to fulfill this requirement. Dysfunctional mitochondria trigger problems in various neuronal tasks. Using the Drosophila neuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth. Here we report tissue-specific adaptations at the NMJ when MCI is depleted. In Drosophila motor neurons, MCI depletion causes profound cytological defects and increased mitochondrial reactive oxygen species (ROS). But instead of diminishing synapse function, neuronal ROS triggers a homeostatic signaling process that maintains normal NMJ excitation. We identify molecules mediating this compensatory response. MCI depletion in muscles also enhances local ROS. But high levels of muscle ROS cause destructive responses: synapse degeneration, mitochondrial fragmentation, and impaired neurotransmission. In humans, mutations affecting MCI subunits cause severe neurological and neuromuscular diseases. The tissue-level effects that we describe in the Drosophila system are potentially relevant to forms of mitochondrial pathogenesis.

Keywords:  Drosophila; Mito-GFP; Mitochondrial Complex I; NACA; ND-20L; ROS; homeostatic plasticity; mitochondria; rotenone; sod2

DOI:  https://doi.org/10.1101/2024.12.30.630694
J Appl Physiol (1985). 2025 Jan 16.

Effects of leg immobilization and recovery resistance training on skeletal muscle-molecular markers in previously resistance trained versus untrained adults.

J Max Michel, Joshua S Godwin, Daniel L Plotkin, Mason C McIntosh, Madison L Mattingly, Philip J Agostinelli, Breanna J Mueller, Derick A Anglin, Nicholas J Kontos, Alexander C Berry, Marina Meyer Vega, Autumn A Pipkin, Matt S Stock, Zachary A Graham, Harsimran S Baweja, C Brooks Mobley, Marcas M Bamman, Michael D Roberts.

  We sought to examine how resistance training (RT) status in young healthy individuals, either well resistance trained (T, n=10) or untrained (UT, n=11), affected molecular markers with leg immobilization followed by recovery RT. All participants underwent two weeks of left leg immobilization via a locking leg brace. Afterwards, all participants underwent eight weeks (3 d/week) of knee extensor focused progressive RT. Vastus lateralis (VL) ultrasound-derived thickness and muscle cross-sectional area were measured at baseline (PRE), immediately after disuse (MID), and after RT (POST) with VL muscle biopsies also being collected at these time points. Both groups presented lower ultrasound derived VL size metrics at MID versus PRE (p<0.001), and values increased in both groups from MID to POST (p<0.05); however, VL size increased from PRE to POST in UT only (p<0.001). Mean and type II myofiber cross-sectional area values were greater at PRE and POST versus MID (p<0.05), with T being greater than UT throughout (P<0.012). In both groups, satellite cell number was not affected by leg immobilization but increased in response to RT (p<0.014), with T being greater than UT throughout (p=0.004). Total RNA (ribosome content) decreased (p=0.010) from PRE to MID, while total RNA and certain endoplasmic reticulum stress proteins increased from MID to POST regardless of training status. Immobilization-induced muscle atrophy and recovery RT hypertrophy outcomes are similar between UT and T participants, and the lack of molecular signature differences between groups supports these findings. However, results are limited to younger adults undergoing non-complicated disuse.

Keywords:  atrophy; bracing; hypertrophy; immobilization

DOI:  https://doi.org/10.1152/japplphysiol.00837.2024
Immunity. 2025 Jan 14. pii: S1074-7613(24)00571-5. [Epub ahead of print]58(1): 5-7

Mitochondria and NLRP3: To die or inflame.

Shuangshuang Yang, Guannan Huang, Jenny P-Y Ting.

Mitochondria play critical roles in intrinsic apoptosis and NLRP3 inflammasome activation, but how these processes are interconnected remains unclear. In this issue of Immunity, Saller et al. unveiled the complexity of NLRP3 activators, highlighting mitochondria's roles in switching apoptosis to NLRP3 inflammasome activation.

DOI: https://doi.org/10.1016/j.immuni.2024.12.007
Ultrasound Med Biol. 2025 Jan 14. pii: S0301-5629(24)00471-X. [Epub ahead of print]

Changes in Muscle Quality Following Short-Term Resistance Training in Older Adults: A Comparison of Echo Intensity and Texture Analysis.

Kevan S Knowles, Jason I Pagan, Jonathan P Beausejour, Scott J Mongold, Abigail W Anderson, Jeffrey R Stout, Matt S Stock.

   BACKGROUND: Skeletal muscle echo intensity (EI) is associated with functional outcomes in older adults, but resistance training interventions have shown mixed results. Texture analysis has been proposed as a novel approach for assessing muscle quality, as it captures spatial relationships between pixels. It is unclear whether texture analysis is able to track changes following resistance training.
OBJECTIVE: To examine changes in first-order (EI) and second-order (texture) features of muscle quality following lower-body resistance training in older adults.
METHODS: Twelve older adults (2 males, 10 females; mean ± SD age = 70 ± 5 years) completed 6 weeks of resistance training, consisting of twice-weekly sessions at 85% of estimated 1RM. Testing included ultrasound imaging of the rectus femoris (RF) and vastus lateralis (VL), 5-repetition maximum (5RM) leg extension strength, and maximal voluntary isometric contraction (MVIC) force. Ultrasound images were analyzed for EI and texture features using gray-level co-occurrence matrix (GLCM) analysis.
RESULTS: Large improvements were observed in 5RM leg extension strength (p < 0.001, effect size [ES] = 2.09), MVIC force (p = 0.006, ES = 0.969), and RF EI (uncorrected: p = 0.003, ES = 0.727; corrected: p = 0.012, ES = 0.864). No significant changes were observed in muscle size, VL EI, or texture features for either muscle.
CONCLUSION: Short-term resistance training improved strength and RF EI. However, texture analysis features were not sensitive to changes following training. These findings suggest that traditional EI measures may be more appropriate than texture analysis for tracking changes in muscle quality following resistance training in older adults.

Keywords:  Aging; Quadriceps; Sarcopenia; Strength training; Ultrasonography

DOI:  https://doi.org/10.1016/j.ultrasmedbio.2024.12.012
Nutr Metab Cardiovasc Dis. 2024 Dec 17. pii: S0939-4753(24)00470-8. [Epub ahead of print] 103836

Obesity as an influencing factor for the occurrence of caffeine-induced effects in women.

Przemysław Domaszewski, Mariusz Konieczny, Paweł Pakosz, Jakub Matuska, Elżbieta Skorupska, Manel M Santafé.

   BECKGROUND AND AIMS: Individuals with a higher body fat percentage may have higher serum levels of caffeine and its metabolites and process caffeine more slowly than individuals with a lower body fat percentage, so the aim of this study is to compare the occurrence of positive and negative effects of caffeine in nonobese and obese women.
METHODS AND RESULTS: One hundred and sixty women were included in the study. Body fat was determined using the mBCA 515 SECA analyzer. Participants were divided into 4 groups: nonobese caffeine, nonobese placebo, obese caffeine and obese placebo. Caffeine groups received 6 mg/kg body weight caffeine. Placebo groups received identical starch-filled capsules. One hour after ingestion and within 24 h, participants completed a caffeine-induced effect questionnaire. Caffeine intake showed statistically significant differences compared to placebo for neutral (p ≤ 0.014; Cramér's V = 0.27; 27 % increase), negative (p ≤ 0.002; Cramér's V = 0.34; 34 % increase), and positive effects (p ≤ 0.015; Cramér's V = 0.27; 27 % increase). Further analysis revealed significant associations with increased urine output (p ≤ 0.014; Cramér's V = 0.27; 27 % increase), vigor/activeness (p ≤ 0.009; Cramér's V = 0.29; 29 % increase), and headache (p ≤ 0.033; Cramér's V = 0.24; 24 % increase) 1 h post-ingestion. No significant effects were observed in the placebo group. There was no statistically significant placebo effect.
CONCLUSIONS: Obese and nonobese women show different responses to caffeine 60 min after ingesting 6 mg/kg body weight. Obese women are more likely to report adverse effects, including increased urine output, heightened vigor/activeness, and headaches, compared to nonobese women.
TRIAL REGISTRATION: ANZCTR12622000823774; June 10, 2022.

Keywords:  Caffeine; Free fat mass; Gender; Overweight; Side effects

DOI:  https://doi.org/10.1016/j.numecd.2024.103836
STAR Protoc. 2025 Jan 10. pii: S2666-1667(24)00714-7. [Epub ahead of print]6(1): 103549

Protocol for the three-dimensional analysis of rodent skeletal muscle.

Smrithi Karthikeyan, Yoko Asakura, Mayank Verma, Atsushi Asakura.

  Confocal imaging is a powerful tool capable of analyzing cellular spatial data within a given tissue. Here, we present a protocol for preparing optically cleared extensor digitorum longus (EDL) skeletal muscle samples suitable for confocal imaging/computational analysis. We describe steps for sample preparation (including perfusion fixation and tissue clearing of muscle samples), image acquisition, and computational analysis, with sample segmentation/3D rendering outlined. This protocol can be applied to characterize various cell types, including muscle satellite cells (muscle stem cells) and capillary endothelial cells within rodent skeletal muscle. For complete details on the use and execution of this protocol, please refer to Verma et al.,1 Verma et al.,2 Karthikeyan et al.,3 and Karthikeyan et al.4.

Keywords:  cell differentiation; classification Description: cell biology; developmental biology; model organisms; molecular biology; stem cells

DOI:  https://doi.org/10.1016/j.xpro.2024.103549
Int J Mol Sci. 2025 Jan 06. pii: 414. [Epub ahead of print]26(1):

Role of PI3 Kinases in Cell Signaling and Soleus Muscle Atrophy During Three Days of Unloading.

Ksenia A Zaripova, Svetlana P Belova, Tatiana Y Kostrominova, Boris S Shenkman, Tatiana L Nemirovskaya.

  During skeletal muscle unloading, phosphoinositide 3-kinase (PI3K), and especially PI3K gamma (PI3Kγ), can be activated by changes in membrane potential. Activated IP3 can increase the ability of Ca2+ to enter the nucleus through IP3 receptors. This may contribute to the activation of transcription factors that initiate muscle atrophy processes. LY294002 inhibitor was used to study the role of PI3K in the ATP-dependent regulation of skeletal muscle signaling during three days of unloading. Inhibition of PI3K during soleus muscle unloading slows down the atrophic processes and prevents the accumulation of ATP and the expression of the E3 ubiquitin ligase MuRF1 and ubiquitin. It also prevents the increase in the expression of IP3 receptors and regulates the activity of Ca2+-dependent signaling pathways by reducing the mRNA expression of the Ca2+-dependent marker calcineurin (CaN) and decreasing the phosphorylation of CaMKII. It also affects the regulation of markers of anabolic signaling in unloaded muscles: IRS1 and 4E-BP. PI3K is an important mediator of skeletal muscle atrophy during unloading. Developing strategies for the localized skeletal muscle release of PI3K inhibitors might be one of the future treatments for inactivity and disease-induced muscle atrophy.

Keywords:  ATP; MuRF1; PI3 kinase; muscle atrophy; unloading

DOI:  https://doi.org/10.3390/ijms26010414