bims-kimdis 2024-12-15 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–12–15
nineteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic diet in treating sepsis-related acquired weakness: is it friend or foe?
Differential effects of short-term and long-term ketogenic diet on gene expression in the aging mouse brain.
Impact of short-term ketogenic diet on sex hormones and glucose-lipid metabolism in overweight or obese patients with polycystic ovary syndrome.
Melatonin protects bovine oocyte from βHB-induced oxidative stress through the Nrf2 pathway.
Sulforaphane, Urolithin A, and ZLN005 induce time-dependent alterations in antioxidant capacity, mitophagy, and mitochondrial biogenesis in muscle cells.
Intermittent and periodic fasting in the treatment of obesity and type 2 diabetes mellitus.
Fasting can reduce weight - but also hair growth.
Leg immobilization and subsequent recovery resistance training affect skeletal muscle angiogenesis related markers in young healthy adults regardless of prior resistance training experience.
Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
Tissue specific roles of fatty acid oxidation.
How fast is your brain ageing? Proteins in blood offer clues.
The CB1 antagonist Rimonabant improves muscle regeneration and remodels the inflammatory and endocannabinoid profile upon injury in male mice.
Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.
Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age.
Low Carbohydrate Availability Promotes a Distinct Circulating microRNA Profile 24 Hours Following Aerobic Exercise.
Comparison of physiological and biochemical changes in old and young hyperglycemic rats submitted to aerobic exercise and anabolic steroid use.
The skeletal muscle proteomic determinants of neuromuscular function in young and older women following 8 weeks of resistance training.
Conserved and Unique Mitochondrial Target Sequence of TRPV4 Can Independently Regulate Mitochondrial Functions.
Exercise alleviates cognitive decline of natural aging rats by upregulating Notch-mediated autophagy signaling.

Front Nutr. 2024 ;11 1484856

Ketogenic diet in treating sepsis-related acquired weakness: is it friend or foe?

Yanmei Miao, Leiyu Xie, Shaolin Chen, Xiaoming Zhang, Wenjie Liu, Peng Xie.

   Background: Sepsis is the body's extreme response to an infection leading to organ dysfunction. Sepsis-related acquired weakness (SAW), a critical illness closely related to metabolic disorders, is characterized by generalized sepsis-induced skeletal muscle weakness, mainly manifesting as symmetrical atrophy of respiratory and limb muscles. Muscle accounts for 40% of the body's total mass and is one of the major sites of glucose and energy absorption. Diet affects skeletal muscle metabolism, which further impacts physiology and signaling pathways. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that has shown benefits in patients with a variety of neuromuscular disorders. Patients with SAW are in a hypermetabolic state and can consume approximately 1% of total body muscle mass in a day. Due to the decreased total body energy expenditure secondary to starvation, skeletal muscles enter a low metabolic state, with reduced gluconeogenesis and protein consumption and elevated levels of ketone bodies. The latest research suggests that KD may be a new strategy for SAW prevention and treatment, but its mechanism is still unclear.
Objective: Our article aims to explore the effect and mechanism of KD on SAW. And we hope that our review will inspire further research on the KD and foster the exploration of novel strategies for combating SAW.
Methods: Search medical databases and related academic websites, using keywords such as "Sepsis-related acquired weakness," "ketogenic diet," and "skeletal muscle," and select representative literature. Using the method of induction and summary, analyze the effect and mechanism of KD on SAW.
Results: Compared with early nutrition, KD has a more protective effect on SAW, but its mechanism is complex. Firstly, KD can alter energy metabolism substrates to affect SAW's energy metabolism; Secondly, KD can directly act as a signaling molecule to improve mitochondrial function in skeletal muscle and stimulate skeletal muscle regeneration signaling molecules; Thirdly, KD can affect the gut microbiota to exert anti-inflammatory effects, enhance immunity, and thus protect SAW.
Conclusion: KD has a protective effect on SAW, which includes improving energy metabolism, stimulating muscle regeneration signals, optimizing gut microbiota composition, and reducing inflammation and oxidative stress.

Keywords:  ICU-acquired weakness; gut microbiota; ketogenic diet; ketone bodies; sepsis-related acquired weakness

DOI:  https://doi.org/10.3389/fnut.2024.1484856
J Nutr Health Aging. 2024 Dec 10. pii: S1279-7707(24)00515-3. [Epub ahead of print]29(2): 100427

Differential effects of short-term and long-term ketogenic diet on gene expression in the aging mouse brain.

Matthew S Stratton, José Alberto López-Domínguez, Alessandro Canella, Jon J Ramsey, Gino A Cortopassi.

   BACKGROUND: Aging is associated with multiple neurodegenerative conditions that severely limit quality of life and can shorten lifespan. Studies in rodents indicate that in addition to extending lifespan, the ketogenic diet (KD) improves cognitive function in aged animals, yet long term adherence to KD in Humans is poor.
OBJECTIVES: To broadly investigate what mechanisms might be activated in the brain in response to ketogenic diet.
METHODS: We conducted transcriptome wide analysis on whole brain samples from 13-month-old mice, 13-month-old mice fed a ketogenic diet for 1 month, 26-month-old mice, and 26-month-old mice fed a ketogenic diet for 14 months.
RESULTS: As expected, analysis of differently expressed genes between the old (26 month) vs younger mice (13 month) showed clear activation of inflammation and complement system pathways with aging. Analysis between the 26-month-old animals fed ketogenic diet for 14 months with 26-month-old animals fed control diet indicate that long-term KD resulted in activation of LRP, TCF7L2 (WNT pathway), and IGF1 signaling. There was also a significant increase in the expression of SOX2-dependent oligodendrocyte/myelination markers, though TCF7L2 and SOX2 dependent gene sets were largely overlapping. Remarkably, the effect of 1 month of ketogenic diet was minimal and there was no congruence between gene expression effects of short-term KD vs long-term KD.
CONCLUSIONS: This work informs target identification efforts for aging and neurodegenerative disorder therapeutics discovery while also establishing differential effects of short-term vs long-term KD on gene expression in the brain.

Keywords:  Brain aging; Ketogenic diet; Target discovery; Transcriptomics

DOI:  https://doi.org/10.1016/j.jnha.2024.100427
J Obstet Gynaecol Res. 2025 Jan;51(1): e16178

Impact of short-term ketogenic diet on sex hormones and glucose-lipid metabolism in overweight or obese patients with polycystic ovary syndrome.

Meng Li, Lisong Zhang, Xiaoyu Li, Yanzhong Zhao.

   AIM: This study evaluates the clinical effects of a ketogenic diet (KD) versus a traditional comprehensive intervention, including lifestyle changes and oral contraceptives, in overweight or obese polycystic ovary syndrome (PCOS) patients.
METHODS: A retrospective analysis of 70 overweight/obese PCOS patients (body mass index [BMI] ≥24 kg/m2) treated between December 2022 and December 2023 was conducted. The patients were categorized into two groups based on their past treatment modality: Group 1 received a KD treatment (N = 35), and Group 2 underwent comprehensive intervention (N = 35), with both treatments lasting 3 months. Changes in body weight, BMI, sex hormone levels, glucose-lipid metabolism indicators, and liver and kidney function were compared.
RESULTS: Both groups experienced significant reductions in body weight and BMI after treatment (p < 0.05), with the KD group showing a greater reduction (p < 0.05). luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), and total testosterone (TT) levels decreased significantly in both groups (p < 0.05). The KD treatment led to significant reductions in fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) (p < 0.05), while the comprehensive intervention resulted in decreased FBG and ALT, and increased high-density lipoprotein-cholesterol (HDL-c) (p < 0.05). Additionally, the KD group had a greater reduction in FBG, and showed decreases in TG and AST, which remained unchanged in the comprehensive intervention group (p < 0.05).
CONCLUSION: The short-term KD treatment provides significant weight loss and effectively improves hormone regulation and glucose-lipid metabolism in overweight or obese PCOS patients, offering a valuable therapeutic option for managing the condition.

Keywords:  glucose metabolism; ketogenic diet; lipid metabolism; polycystic ovary syndrome; sex hormone

DOI:  https://doi.org/10.1111/jog.16178
Theriogenology. 2024 Dec 02. pii: S0093-691X(24)00487-4. [Epub ahead of print]234 64-72

Melatonin protects bovine oocyte from βHB-induced oxidative stress through the Nrf2 pathway.

Kaiyan Zhang, Jing Guo, Simin Wang, Changguo Min, Jun Wang, Hongyu Liu, Yi Fang, He Ding, Jing Zhao, Xin Ma, Wenfa Lu.

  Accumulation of ketone bodies in the blood or tissues can trigger ketosis, exerting detrimental effects on bovine oocytes maturation. Exposure to its primary component, β-hydroxybutyric acid (βHB), disrupts mitochondrial function, culminating in the excessive buildup of reactive oxygen species (ROS) and subsequent initiation of apoptosis in oocytes. These ultimately result in poor oocyte quality. Melatonin, recognized for its endogenous antioxidant properties, is capable of mitigating ROS levels and enhancing the expression of antioxidant enzymes. In this study, we explored the protective effects of melatonin on the damages induced by βHB. Melatonin was added at a concentration of 10-9 M to the culture medium on bovine oocytes. Parameters including first polar body extrusion rate, mitochondrial membrane potential, ROS, cell apoptosis were assessed. Results showed that melatonin could restore bovine oocyte maturation rate, enhance mitochondrial function, reduce cell apoptosis rate, and mitigate oxidative stress levels. Notably, Nrf2 signaling pathway inhibitor ML385 significantly attenuated the protective effects of melatonin on oxidative stress induced by βHB exposure. In summary, our study demonstrates that melatonin can protect oocytes from oxidative stress induced by βHB exposure, with indications that this protective mechanism may be mediated through the Nrf2 pathway.

Keywords:  Bovine; Melatonin; Nrf2; Oocyte; β-hydroxybutyric acid (βHB)

DOI:  https://doi.org/10.1016/j.theriogenology.2024.11.025
Sports Med Health Sci. 2025 Jan;7(1): 16-27

Sulforaphane, Urolithin A, and ZLN005 induce time-dependent alterations in antioxidant capacity, mitophagy, and mitochondrial biogenesis in muscle cells.

Neushaw Moradi, Sabrina Champsi, David A Hood.

  Efficient signal transduction that mediates mitochondrial turnover is a strong determinant of metabolic health in skeletal muscle. Of these pathways, our focus was aimed towards the enhancement of antioxidant capacity, mitophagy, and mitochondrial biogenesis. While physical activity is an excellent inducer of mitochondrial turnover, its ability to ubiquitously activate and enhance mitochondrial turnover prevents definitive differentiation of the contribution made by each pathway. Therefore, we employed three agents, Sulforaphane (SFN), Urolithin A (UroA), and ZLN005 (ZLN), which are activators of important biological markers involved in antioxidant signaling, mitophagy, and biogenesis, respectively. We investigated the time-dependent changes in proteins related to each mechanism in C2C12 myotubes. SFN treatment resulted in increased nuclear localization of the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) after 4 hour (h), with subsequent 2-fold increases in the antioxidant enzymes Nicotinamide Quinone Oxidoreductase 1 (NQO1) and Heme-Oxygenase-1 (HO-1) by 24 h and 48 h. Mitochondrial respiration and ATP production were significantly increased by both 24 h and 48 h. UroA showed a 2-fold increase in AMP-activated Protein Kinase (AMPK) after 4 h, which led to a modest 30% increase in whole cell mitophagy markers p62 and LC3, after 48 h. This was accompanied by a reduction in cellular Reactive Oxygen Species (ROS), detected with the CellROX Green reagent. Mitophagy flux measurements showed mitophagy activation as both LC3-II and p62 flux increased with UroA at 24-h and 48-h time points, respectively. Finally, AMPK activation was observed by 4 h, in addition to a 2-fold increase in Mitochondrial Transcription Factor A (TFAM) promoter activity by 24 h of ZLN treatment following transient transfection of a TFAM promoter-luciferase construct. Mitochondrial respiration and ATP production were enhanced by 24 h. Our results suggest that early time points of treatment increase upstream pathway activity, whereas later time points represent the increased phenotypic expression of related downstream markers. Our findings suggest that the spatiotemporal progression of these mechanisms following drug treatment is another important factor to consider when examining subcellular changes towards mitochondrial turnover in muscle.

Keywords:  AMPK; Exercise mimetic; Mitochondria; Nrf-2; Skeletal muscle

DOI:  https://doi.org/10.1016/j.smhs.2024.03.011
Nat Rev Endocrinol. 2024 Dec 13.

Intermittent and periodic fasting in the treatment of obesity and type 2 diabetes mellitus.

Valter D Longo.

DOI: https://doi.org/10.1038/s41574-024-01078-5
Nature. 2024 Dec 13.

Fasting can reduce weight - but also hair growth.

Max Kozlov.



Keywords:  Cell biology; Metabolism; Regeneration; Stem cells

DOI:  https://doi.org/10.1038/d41586-024-04084-9
bioRxiv. 2024 Nov 26. pii: 2024.11.24.625075. [Epub ahead of print]

Leg immobilization and subsequent recovery resistance training affect skeletal muscle angiogenesis related markers in young healthy adults regardless of prior resistance training experience.

Mason C McIntosh, J Max Michel, Joshua S Godwin, Daniel L Plotkin, Derick A Anglin, Madison L Mattingly, Anthony Agyin-Birikorang, Nicholas J Kontos, Harsimran S Baweja, Matt S Stock, C Brooks Mobley, Michael D Roberts.

We recently reported that resistance trained (T, n=10) and untrained (UT, n=11) young adults experience vastus lateralis (VL) muscle atrophy following two weeks of disuse, and 8 weeks of recovery resistance training (RT) promotes VL hypertrophy in both participant cohorts. However, angiogenesis targets and muscle capillary number were not examined and currently no human studies that have sought to determine if disuse followed by recovery RT affects these outcomes. Thus, we examined whether disuse and/or recovery RT affected these outcomes. All participants underwent two weeks of left leg immobilization using locking leg braces and crutches followed by eight weeks (3d/week) of knee extensor focused progressive RT. VL biopsies were obtained at baseline (PRE), immediately after disuse (MID), and after RT (POST). Western blotting was used to assay angiogenesis markers and immunohistochemistry was performed in 16/21 participants to determine type I and II muscle fiber capillary number. Significant main effects of time (p<0.05) were observed for protein levels of VEGF (MID<POST), VEGFR2 (PRE&MID<POST), TSP-1 (PRE<POST), TIMP1 (MID<POST), phosphorylated/pan eNOS (Ser1177) (POST<PRE), and pan eNOS (PRE<POST). VEGFR2 exhibited a training status*time (p=0.018), but no differences existed between T and UT at any time point. A significant main effect of time was observed for type II fiber capillary number (PRE<POST), and type II fiber cross-sectional area (fCSA) increased from MID to POST (+25%, p<0.001) and PRE to POST (+20%, p=0.019). No significant correlations exist for percentage changes in type II fiber capillary number and type II fCSA from PRE-to-MID (r= 0.020), MID-to-POST (r= 0.392), or PRE-to-POST (r= -0.120) across all participants (p>0.100). Although disuse and recovery RT affect skeletal muscle angiogenesis-related protein targets, prior training history does not differentially affect these outcomes.
NEW AND NOTEWORTHY: This is the first study to examine how limb immobilization and recovery resistance training affect molecular outcomes related to angiogenesis in younger adults with or without a prior training history. Regardless of resistance training history, the molecular responses are largely similar between participant cohorts and is suggestive of a reduced (pre-mid) and increased (mid-post) angiogenic response, with disuse and subsequent recovery resistance training.

DOI: https://doi.org/10.1101/2024.11.24.625075
bioRxiv. 2024 Nov 26. pii: 2024.11.24.625104. [Epub ahead of print]

Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.

Matthew D Campbell, Monica Sanchez-Contreras, Britta D Sibley, Phoebe Keiser, Carla Ruiz Sanchez, Carolyn N Mann, David J Marcinek, Behzad Najafian, Mariya T Sweetwyne.

Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is yet unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state that may stress mitochondria. To address this, we crossed floxed hemagglutinin (HA) -mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or distal tubule and collecting duct (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation. Mitochondrial respiration in fresh isolates from young (4-7 mo) and aged (22-26 mo) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than do tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase (CS) levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Finally, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production of podocyte mitochondria isolated directly from fresh kidneys. Thus, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than mitochondria-dependent tubules per organelle. Previous studies may not have detected these differences due to reliance on podocyte cell culture conditions, which results in artifactual suppression of mitochondrial function.

DOI: https://doi.org/10.1101/2024.11.24.625104
Adv Biol Regul. 2024 Dec 05. pii: S2212-4926(24)00058-7. [Epub ahead of print] 101070

Tissue specific roles of fatty acid oxidation.

Danielle M Smith, Joseph Choi, Michael J Wolfgang.

Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.

DOI: https://doi.org/10.1016/j.jbior.2024.101070
Nature. 2024 Dec 09.

How fast is your brain ageing? Proteins in blood offer clues.

Miryam Naddaf.



Keywords:  Brain; Diseases

DOI:  https://doi.org/10.1038/d41586-024-04055-0
Life Sci. 2024 Dec 05. pii: S0024-3205(24)00886-5. [Epub ahead of print] 123296

The CB1 antagonist Rimonabant improves muscle regeneration and remodels the inflammatory and endocannabinoid profile upon injury in male mice.

Sebastiaan Dalle, Moniek Schouten, Kaat Vanderbeke, Evy Van Parys, Monique Ramaekers, Martine Thomis, Domiziana Costamagna, Katrien Koppo.

  Skeletal muscle regeneration upon injury requires timely activation of inflammatory, myogenic, fibrotic, apoptotic and anabolic systems. Optimization of these features might improve the recovery process. Whereas recent data indicate that the endocannabinoid system, and more particularly cannabinoid receptor 1 (CB1) antagonism, is involved in the regulation of inflammatory, myogenic, fibrotic, apoptotic and anabolic pathways, it was never studied whether CB1 antagonism can improve muscle regeneration. The present study investigated the effect of the CB1 antagonist Rimonabant (10 mg/kg/d) on functional (5 days post-cardiotoxin injury; 5DPI) and molecular muscle responses (3DPI and 7DPI) in mice. Rimonabant prevented cardiotoxin-induced muscle strength loss 5DPI, increased myofiber growth (7DPI) and improved the muscle molecular profile 3DPI and 7DPI. In general, inflammation (e.g. p-p65NF-κB, CD80) and apoptosis (e.g. cleaved caspase-3, cleaved PARP) were downregulated by Rimonabant, whereas it upregulated the expression of Pax7 but other myogenic factors remained unaffected by rimonabant. In addition, Rimonabant restored the injury-induced (inflammatory) lipid profile to a large extent, including oxygenated fatty acids, unsaturated fatty acids and endocannabinoids such as 2-arachidonoyl glycerol and palmitoylethanolamide. Altogether, these data show that the endocannabinoid system might be a novel therapeutic target to improve muscle regeneration, which is relevant for age- and disease-related muscle degeneration.

Keywords:  Cannabinoid receptor 1; Cardiotoxin; Endocannabinoid system; Muscle regeneration; Muscle strength

DOI:  https://doi.org/10.1016/j.lfs.2024.123296
Am J Physiol Cell Physiol. 2024 Dec 13.

Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.

Sabrina Champsi, David A Hood.

  Mitochondria are metabolic hubs that govern skeletal muscle health. While exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined Sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial ROS emission. Signaling towards biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggests that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.

Keywords:  Nrf-2; PGC-1α; exercise; mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00669.2024
Imaging Neurosci (Camb). 2024 ;2

Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age.

Helena van Nieuwenhuizen, Anthony G Chesebro, Claire Polizu, Kieran Clarke, Helmut H Strey, Corey Weistuch, Lilianne R Mujica-Parodi.

  Aging is associated with impaired signaling between brain regions when measured using resting-state fMRI. This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we confirmed their robustness across measurement modalities using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20-80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, μage=26.9±11.2years , N = 36). Then, using a multiscale conductance-based neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels. As such, the approach facilitates the connection between macroscopic brain activity and cellular-level mechanisms.

Keywords:  Aging; Ketone Ester; Metabolism; Multiscale Modeling; Synchrony

DOI:  https://doi.org/10.1162/imag_a_00163
Physiol Genomics. 2024 Dec 11.

Low Carbohydrate Availability Promotes a Distinct Circulating microRNA Profile 24 Hours Following Aerobic Exercise.

Devin J Drummer, Christopher T Carrigan, Nancy E Murphy, Marques A Wilson, Julia Michalak, Claire C Whitney, Donato A Rivas, Stefan M Pasiakos, Lee M Margolis.

  Low carbohydrate availability during recovery from aerobic exercise alters skeletal muscle microRNA (miRNA) profiles, which may mechanistically regulate exercise recovery. However, its impact on circulating miRNA (c-miRNA) profiles remains unclear. Purpose: This study aimed to determine the effects of low versus adequate carbohydrate availability on c-miRNA profiles during recovery from aerobic exercise. Methods: Nine males (22±4yrs, 1.81±0.09m, 83.9±11.9kg, 25.7±2.3kg/m2, mean±SD) completed this randomized, crossover study consisting of two glycogen depletion trials, followed by 24 hours of isocaloric refeeding to induce low (LOW; 1.5 g/kg carbohydrate, 3.0 g/kg fat) or adequate (AD; 6.0 g/kg carbohydrate, 1.0 g/kg fat) carbohydrate availability. Total c-miRNA were extracted from serum 24 hours following glycogen depletion exercise. Data were log transformed and analyzed as fold change relative to AD. Bioinformatics were conducted on significant c-miRNA and associated pathways (miRTarBase/KEGG). Follow-up transfection of miR-375-3p mimic or inhibitor into C2C12 cells assessed metabolic, inflammatory, and catabolic pathways at the gene and protein levels. Results: Of the 84 miRNA assessed, miR-335-5p (-0.49±0.60; P=0.04) and miR-375-3p (-1.57±1.25; P=0.01) were significantly lower, and miR-214-3p (1.76±1.85; P=0.02) was significantly higher in AD versus LOW. In vitro experiments indicated that miR-375-3p regulates catabolic pathways at the gene and protein level. Conclusion: Low carbohydrate availability alters c-miRNA profiles, particularly miR-375-3p, which targets proteostasis and metabolism 24 hours into recovery from aerobic exercise. These findings identify unique c-miRNA targets as potential biomarkers for the mechanistic effects of low carbohydrate availability on exercise recovery.

Keywords:  Dietary intake; epigenetics; exercise recovery; post-transcriptional regulation

DOI:  https://doi.org/10.1152/physiolgenomics.00107.2024
Sports Med Health Sci. 2025 Jan;7(1): 28-36

Comparison of physiological and biochemical changes in old and young hyperglycemic rats submitted to aerobic exercise and anabolic steroid use.

Carolina Freitas da Silva, Morun Bernardino-Neto, Thiago Montes Fidale, Anibal Monteiro de Magalhães Neto, João Rafael Valentim-Silva, Yuri Karaccas de Carvalho, Rodrigo Daminello Raimundo, Luiz Carlos de Abreu, Romeu Paulo Martins Silva, Nilson Penha-Silva.

  Prolonged hyperglycemia conditions are a risk factor for chronic degenerative diseases such as diabetes and obesity. Testosterone is known to cause muscle hypertrophy, reduced fat mass, and increased body strength. The study aimed to verify possible alterations and differences in the influence of testosterone on the physical performance in post-exercise conditions of young and old animals with alloxan-induced hyperglycemia. We randomly assigned 32 young Wistar rats to groups of untreated non-diabetic young, treated non-diabetic young, untreated diabetic young, and treated diabetic young rats, and 32 aged Wistar rats to groups of untreated non-diabetic elderly, treated non-diabetic elderly, untreated diabetic elderly, and treated diabetic elderly rats, with eight animals each group. The treated non-diabetic and treated diabetic groups received injections of 15 mg/kg weight Durateston™. All the trained groups performed aquatic training with an overload of 5% of the body mass. Following the experiment, we anesthetized and euthanized the animals after exercise (exhaustion). Hemoglobin, erythrocytes, and hematocrit values were higher in the treated groups. The treated diabetic elderly group had the highest leukocyte and neutrophil counts compared to the untreated young groups (p < 0.05). As for the lipid profile, untreated rats had the highest values. Glucose concentration was higher at rest and after exercise in the untreated diabetic groups (p < 0.05). Lactate was more elevated in the untreated diabetic groups, and the testosterone-treated groups performed the longest swimming time after the maximal test (p < 0.05). The use of testosterone in conjunction with physical exercise improved physical performance in water, blood glucose, and lipid profiles.

Keywords:  Aging; Anabolics; Diabetes; Exercise; Glucose; Lipid

DOI:  https://doi.org/10.1016/j.smhs.2023.12.007
Exp Physiol. 2024 Dec 11.

The skeletal muscle proteomic determinants of neuromuscular function in young and older women following 8 weeks of resistance training.

Mary O'Leary, Elsa Greed, Jack Pritchard, Lauren Struszczak, Esra Bozbaş, Joanna Bowtell.

  Resistance training (RT) is the gold standard intervention for ameliorating sarcopenia. Outstanding mechanistic questions remain regarding the malleability of the molecular determinants of skeletal muscle function in older age. Discovery of proteomics can expand such knowledge. We aimed to compare the effect of RT on the skeletal muscle proteome and neuromuscular function (NMF) in older and younger women. Seven young (22 ± 6 years) and eight older (63 ± 5 years) women completed 8 weeks' leg RT. Pre- and post-training, measures of leg and handgrip strength, NMF and vastus lateralis (VL) biopsies were obtained. Tandem-mass-tagged skeletal muscle proteomic analyses were performed. Data were analysed using differential expression and weighted gene co-expression network approaches. Proteins related to skeletal muscle contraction were lower in older skeletal muscle; this was not normalised by RT. Following RT, older women had higher expression of VL mitochondrial biogenesis proteins compared to the young, a reversal of pre-training observations. Seventy proteins were differentially expressed between age groups. VL expression of these proteins in older women was consistently and significantly associated with poorer leg strength/NMF. Conversely, VL expression of these proteins in older women was often associated with greater handgrip strength. This study has identified important differences in the molecular responses of young and old skeletal muscle to RT. We have demonstrated their close relationship with skeletal muscle function. Proteins that are refractory to RT may represent targets to ameliorate sarcopenia. We have described a 'proteomic-function' relationship that appears to be muscle-specific. Future research should further unpick these complex relationships.

Keywords:  exercise; proteomics; resistance training; skeletal muscle; strength

DOI:  https://doi.org/10.1113/EP092328
Proteins. 2024 Dec 08.

Conserved and Unique Mitochondrial Target Sequence of TRPV4 Can Independently Regulate Mitochondrial Functions.

Tusar Kanta Acharya, Parnasree Mahapatra, Shamit Kumar, Nishant Kumar Dubey, Srujanika Rajalaxmi, Arijit Ghosh, Ashutosh Kumar, Chandan Goswami.

  Though mitochondria have their own genome and protein synthesis machineries, the majority of the mitochondrial proteins are actually encoded by the nuclear genome. Most of these mitochondrial proteins are imported into specific compartments of the mitochondria due to their mitochondrial target sequence (MTS). Unlike the nuclear target sequence, the MTS of most of the mitochondrial localized proteins remain poorly understood, mainly due to their variability, heterogeneity, unconventional modes of action, mitochondrial potential-dependent transport, and other complexities. Recently, we reported that transient receptor potential vanilloid subtype 4 (TRPV4), a thermosensitive cation channel, is physically located at the mitochondria. Here we characterize a small segment (AA 592-630) located at the TM4-loop4-TM5 segment of TRPV4 that acts as a novel MTS. The same region remains highly conserved in all vertebrates and contains a large number of point mutations each of which causes an diverse spectrum of diseases in human. Using confocal and super-resolution microscopy, we show that this MTS of TRPV4 or its mutants localizes to the mitochondria independently and also induces functional and quantitative changes in the mitochondria. By using conformal microscopy, we could detect the presence of the MTS region within the isolated mitochondria. These findings may be important to understand the complexity of MTS and TRPV4-induced channelopathies better.

Keywords:  Ca2+‐signaling; channelopathy; ion channel; molecular evolution; oxidative potential

DOI:  https://doi.org/10.1002/prot.26772
Brain Res. 2024 Dec 10. pii: S0006-8993(24)00653-X. [Epub ahead of print]1850 149398

Exercise alleviates cognitive decline of natural aging rats by upregulating Notch-mediated autophagy signaling.

Dandan Chen, Yuan Guo, Meng Zhang, Xingran Liu, Baowen Zhang, Xianjuan Kou.

  Notch signaling, a classical signaling pathway of neurogenesis, is downregulated during the aging and age-related neurodegenerative diseases. Exercise has been proposed as an effective lifestyle intervention for delaying cognitive decline. However, it remains unclear whether exercise intervention could alleviate cognitive decline by modulating neurogenesis in naturally aging rats. In this study, 21-month-old natural aging rats were used to study brain aging. The natural aging rats underwent different forms of exercise training (aerobic exercise or strength training or comprehensive exercise with aerobic exercise and strength training) for 12 consecutive weeks. The cognitive function of natural aging rats was determined by Morris Water Maze. Notch signaling, autophagy-related proteins and hippocampal neurogenesis were examined by immunofluorescence, qRT-PCR and Western blot. Results showed that natural aging rats exhibited cognitive decline, accumulation of AD pathological proteins (APP and Aβ), and decreased neurogenesis (decreased DCX, Ki67 and GFAP), compared with the young control rats. Moreover, a significant decline in Notch signaling and autophagy was found in the hippocampus of natural aging rats. However, different forms of exercise upregulated Notch signaling and its downstream target genes, as well as autophagy-related proteins, including LC3, Beclin1, and p62. In summary, our data suggest that different forms of exercise can mitigate brain aging by upregulating Notch signaling and autophagy, thereby increasing hippocampal neurogenesis and improves spatial learning and memory abilities.

Keywords:  Autophagy; Cognitive dysfunction; Exercise intervention; Notch signaling

DOI:  https://doi.org/10.1016/j.brainres.2024.149398