bims-kimdis 2023-11-26 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒11‒26
fourteen papers selected by
Matías Javier Monsalves Álvarez

Defining ketone supplementation: the evolving evidence for post-exercise ketone supplementation to improve recovery and adaptation to exercise.
Does the ketogenic diet improve neurological disorders by influencing gut microbiota? A systematic review.
Is ketogenic diet a 'precision medicine'? Recent developments and future challenges.
The Ketogenic Effect of SGLT-2 Inhibitors-Beneficial or Harmful?
Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy.
β-hydroxybutyrate administered at reperfusion reduces infarct size and preserves cardiac function by improving mitochondrial function through autophagy in male mice.
Liver-Derived Ketogenesis via Overexpressing HMGCS2 Promotes the Recovery of Spinal Cord Injury.
The effect of acute and 14-day exogenous ketone supplementation on glycaemic control in adults with type 2 diabetes: two randomized controlled trials.
Dietary triacetin, but not medium chain triacylglycerides, blunts weight gain in diet-induced rat model of obesity.
The mitochondrial calcium uniporter is necessary for synaptic plasticity and proper mitochondrial morphology and distribution in the distal dendrites of CA2 neurons.
Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA).
The Molecular Mechanisms of Fuel Utilization during Exercise.
MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism.
Hallmarks of ageing in human skeletal muscle and implications for understanding the pathophysiology of sarcopenia in women and men.

Am J Physiol Cell Physiol. 2023 Nov 20.

Defining ketone supplementation: the evolving evidence for post-exercise ketone supplementation to improve recovery and adaptation to exercise.

Ruben Robberechts, Chiel Poffé.

  Over the last decade, there has been a growing interest in the use of ketone supplements to improve athletic performance. These ketone supplements transiently elevate the concentrations of the ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) in the circulation. Early studies showed that ketone bodies can improve energetic efficiency in striated muscle compared to glucose oxidation and induce a glycogen-sparing effect during exercise. As such, most research has focused on the potential of ketone supplementation to improve athletic performance via ingestion of ketones immediately before or during exercise. However, subsequent studies generally observed no performance improvement, and particularly not under conditions that are relevant for most athletes. However, more and more studies are reporting beneficial effects when ketones are ingested after exercise. As such, the real potential of ketone supplementation may rather be in their ability to enhance post-exercise recovery and training adaptations. For instance, recent studies observed that post-exercise ketone supplementation (PEKS) blunts the development of overtraining symptoms, and improves sleep, muscle anabolic signaling, circulating erythropoietin levels, and skeletal muscle angiogenesis. In this review, we provide an overview of the current state-of-the-art about the impact of PEKS on aspects of exercise recovery and training adaptation, which is not only relevant for athletes but also in multiple clinical conditions. In addition, we highlight the underlying mechanisms by which PEKS may improve exercise recovery and training adaptation. This includes epigenetic effects, signaling via receptors, modulation of neurotransmitters, energy metabolism, and oxidative and anti-inflammatory pathways.

Keywords:  acetoacetate; exercise recovery; post-exercise ketosis; training adaptations; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00485.2023
Nutr J. 2023 Nov 20. 22(1): 61

Does the ketogenic diet improve neurological disorders by influencing gut microbiota? A systematic review.

Mahdi Mazandarani, Narges Lashkarbolouk, Hanieh-Sadat Ejtahed, Mostafa Qorbani.

  BACKGROUND: The aim of this systematic review is to evaluate the changes in gut microbiota (GM) induced by the Ketogenic Diets (KD) as a potential underlying mechanism in the improvement of neurological diseases.METHODS: A comprehensive search was conducted on three electronic databases, including PubMed/Medline, Web of Science, and Scopus until December 2022. The inclusion criteria were studies that described any changes in GM after consuming KD in neurological patients. Full text of studies such as clinical trials and cohorts were added. The quality assessment of cohort studies was conducted using the Newcastle-Ottawa Quality Assessment Scale and for the clinical trials using the Cochrane Collaboration tool. The search, screening, and data extraction were performed by two researchers independently.
RESULTS: Thirteen studies examining the effects of the KD on the GM in neurological patients were included. Studies have shown that KD improves clinical outcomes by reducing disease severity and recurrence rates. An increase in Proteobacteria phylum, Escherichia, Bacteroides, Prevotella, Faecalibacterium, Lachnospira, Agaricus, and Mrakia genera and a reduction in Firmicutes, and Actinobacteria phyla, Eubacterium, Cronobacter, Saccharomyces, Claviceps, Akkermansia and Dialister genera were reported after KD. Studies showed a reduction in concentrations of fecal short-chain fatty acids and branched-chain fatty acids and an increase in beta Hydroxybutyrate, trimethylamine N-oxide, and N-acetylserotonin levels after KD.
CONCLUSION: The KD prescribed in neurological patients has effectively altered the GM composition and GM-derived metabolites.

Keywords:  Gut microbiota; Ketogenic diet; Ketones; Neurodegenerative diseases

DOI:  https://doi.org/10.1186/s12937-023-00893-2
Eur J Paediatr Neurol. 2023 Nov 15. pii: S1090-3798(23)00164-2. [Epub ahead of print]48 13-16

Is ketogenic diet a 'precision medicine'? Recent developments and future challenges.

Network for Therapy in Rare Epilepsies (NETRE)

  Recently, precision medicine has attracted much attention in the management of epilepsies, but it remains unclear if the increasingly utilized ketogenic diet approaches can truly be considered precision medicine in all epilepsy treatment. Currently, it is the standard treatment for patients with GLUT1 deficiency and the latest NICE guidelines highlight ketogenic diet as a therapeutic option for multi-drug resistant epilepsy patients. Ketogenic diet is presumed to be a precision medicine tool when applied to the treatment of seizures secondary to GLUT1 transporter deficiency. In contrast, the genetic and epigenetic mechanisms modulated by ketogenic diet and underlying its efficacy in other epilepsy types can only be hypothesized to relate to mechanisms of neuroprotection, neuromodulation, and reduction of neuroinflammation. Early ketogenic diet initiation in well-selected patients, would allow immediate action in the direction of neuroprotection and modulation of neuroinflammation, ensuring higher success rates and lower "cost" to the patient in terms of quality of life and comorbidities. These considerations have fueled an increasing interest in investigating the efficacy, side effects, and adherence to long-term use of the ketogenic diet in epilepsy treatment in large contemporary cohorts, available within the scope of multicentric collaborations, such as the European Network for Therapy in Rare Epilepsies (NETRE). Future directions should involve the use of precision medicine, applied to each patient with the help of "omics", whose use should be expanded and inclusive.

Keywords:  Drug-resistant epilepsy; GLUT-1; Ketogenic diet; Precision medicine; Transcriptomic profile

DOI:  https://doi.org/10.1016/j.ejpn.2023.11.002
J Cardiovasc Dev Dis. 2023 Nov 16. pii: 465. [Epub ahead of print]10(11):

The Ketogenic Effect of SGLT-2 Inhibitors-Beneficial or Harmful?

Michail Koutentakis, Jakub Kuciński, Damian Świeczkowski, Stanisław Surma, Krzysztof J Filipiak, Aleksandra Gąsecka.

  Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, also called gliflozins or flozins, are a class of drugs that have been increasingly used in the management of type 2 diabetes mellitus (T2DM) due to their glucose-lowering, cardiovascular (CV), and renal positive effects. However, recent studies suggest that SGLT-2 inhibitors might also have a ketogenic effect, increasing ketone body production. While this can be beneficial for some patients, it may also result in several potential unfavorable effects, such as decreased bone mineral density, infections, and ketoacidosis, among others. Due to the intricate and multifaceted impact caused by SGLT-2 inhibitors, this initially anti-diabetic class of medications has been effectively used to treat both patients with chronic kidney disease (CKD) and those with heart failure (HF). Additionally, their therapeutic potential appears to extend beyond the currently investigated conditions. The objective of this review article is to present a thorough summary of the latest research on the mechanism of action of SGLT-2 inhibitors, their ketogenesis, and their potential synergy with the ketogenic diet for managing diabetes. The article particularly discusses the benefits and risks of combining SGLT-2 inhibitors with the ketogenic diet and their clinical applications and compares them with other anti-diabetic agents in terms of ketogenic effects. It also explores future directions regarding the ketogenic effects of SGLT-2 inhibitors.

Keywords:  SGLT-2 inhibitors (gliflozins); T2DM; benefits; cardiovascular; heart failure; infections; ketogenesis; ketogenic diet; kidney disease; risks

DOI:  https://doi.org/10.3390/jcdd10110465
Int J Mol Sci. 2023 Nov 09. pii: 16142. [Epub ahead of print]24(22):

Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy.

Ting-I Lee, Nguyen Ngoc Trang, Ting-Wei Lee, Satoshi Higa, Yu-Hsun Kao, Yao-Chang Chen, Yi-Jen Chen.

  A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca2+) homeostasis. We investigated the effects of a KD on Ca2+ homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD. Our electrophysiological and Western blot analyses assessed myocardial Ca2+ homeostasis in ventricular preparations in vivo. Unlike those on the KD, DM rats treated with an ND exhibited a prolonged QTc interval and action potential duration. Compared to the control and DM rats on the KD, DM rats treated with an ND also showed lower intracellular Ca2+ transients, sarcoplasmic reticular Ca2+ content, sodium (Na+)-Ca2+ exchanger currents (reverse mode), L-type Ca2+ contents, sarcoplasmic reticulum ATPase contents, Cav1.2 contents. Furthermore, these rats exhibited elevated ratios of phosphorylated to total proteins across multiple Ca2+ handling proteins, including ryanodine receptor 2 (RyR2) at serine 2808, phospholamban (PLB)-Ser16, and calmodulin-dependent protein kinase II (CaMKII). Additionally, DM rats treated with an ND demonstrated a higher frequency and incidence of Ca2+ leak, cytosolic reactive oxygen species, Na+/hydrogen-exchanger currents, and late Na+ currents than the control and DM rats on the KD. KD treatment may attenuate the effects of DM-dysregulated Na+ and Ca2+ homeostasis, contributing to its cardioprotection in DM.

Keywords:  arrhythmias; calcium homeostasis; diabetic cardiomyopathy; electrophysiology; ketogenic diet

DOI:  https://doi.org/10.3390/ijms242216142
J Mol Cell Cardiol. 2023 Nov 16. pii: S0022-2828(23)00169-4. [Epub ahead of print]186 31-44

β-hydroxybutyrate administered at reperfusion reduces infarct size and preserves cardiac function by improving mitochondrial function through autophagy in male mice.

Yuxin Chu, Yutao Hua, Lihao He, Jin He, Yunxi Chen, Jing Yang, Ismail Mahmoud, Fanfang Zeng, Xiaochang Zeng, Gloria A Benavides, Victor M Darley-Usmar, Martin E Young, Scott W Ballinger, Sumanth D Prabhu, Cheng Zhang, Min Xie.

  Ischemia/reperfusion (I/R) injury after revascularization contributes ∼50% of infarct size and causes heart failure, for which no established clinical treatment exists. β-hydroxybutyrate (β-OHB), which serves as both an energy source and a signaling molecule, has recently been reported to be cardioprotective when administered immediately before I/R and continuously after reperfusion. This study aims to determine whether administering β-OHB at the time of reperfusion with a single dose can alleviate I/R injury and, if so, to define the mechanisms involved. We found plasma β-OHB levels were elevated during ischemia in STEMI patients, albeit not to myocardial protection level, and decreased after revascularization. In mice, compared with normal saline, β-OHB administrated at reperfusion reduced infarct size (by 50%) and preserved cardiac function, as well as activated autophagy and preserved mtDNA levels in the border zone. Our treatment with one dose β-OHB reached a level achievable with fasting and strenuous physical activity. In neonatal rat ventricular myocytes (NRVMs) subjected to I/R, β-OHB at physiologic level reduced cell death, increased autophagy, preserved mitochondrial mass, function, and membrane potential, in addition to attenuating reactive oxygen species (ROS) levels. ATG7 knockdown/knockout abolished the protective effects of β-OHB observed both in vitro and in vivo. Mechanistically, β-OHB's cardioprotective effects were associated with inhibition of mTOR signaling. In conclusion, β-OHB, when administered at reperfusion, reduces infarct size and maintains mitochondrial homeostasis by increasing autophagic flux (potentially through mTOR inhibition). Since β-OHB has been safely tested in heart failure patients, it may be a viable therapeutic to reduce infarct size in STEMI patients.

Keywords:  Autophagy; Ischemia-reperfusion injury; Mitochondria; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.yjmcc.2023.11.001
Adv Biol (Weinh). 2023 Nov 22. e2300481

Liver-Derived Ketogenesis via Overexpressing HMGCS2 Promotes the Recovery of Spinal Cord Injury.

Xiaofei Sun, Bin Zhang, Kaiqiang Sun, Fudong Li, Dongping Hu, Juxiang Chen, Fanqi Kong, Yang Xie.

  The liver is the major ketogenic organ of the body, and ketones are reported to possess favorable neuroprotective effects. This study aims to elucidate whether ketone bodies generated from the liver play a critical role in bridging the liver and spinal cord. Mice model with a contusive spinal cord injury (SCI) surgery is established, and SCI induces significant histological changes in mice liver. mRNA-seq of liver tissue shows the temporal changes of ketone bodies-related genes, β-hydroxybutyrate dehydrogenase (BDH1) and solute carrier family 16 (monocarboxylic acid transporters), member 6 (SLC16A6). Then, an activated ketogenesis model is created with adult C57BL/6 mice receiving the tail intravenous injection of GPAAV8-TBG-Mouse-Hmgcs2-CMV- mCherry -WPRE (HMGCS2liver ) and mice receiving equal AAV8-Null being the control group (Vectorliver ). Then, the mice undergo either a contusive SCI or sham surgery. The results show that overexpression of HMG-CoA synthase (Hmgcs2) in mice liver dramatically alleviates SCI-mediated pathological changes and promotes ketogenesis in the liver. Amazingly, liver-derived ketogenesis evidently alleviates neuron apoptosis and inflammatory microglia activation and improves the recovery of motor function of SCI mice. In conclusion, a liver-spinal cord axis can be bridged via ketone bodies, and enhancing the production of the ketone body within the liver has neuroprotective effects on traumatic SCI.

Keywords:  inflammatory response; ketogenesis; liver-spinal cord axis; microglia polarization; spinal cord injury

DOI:  https://doi.org/10.1002/adbi.202300481
Am J Physiol Endocrinol Metab. 2023 Nov 22.

The effect of acute and 14-day exogenous ketone supplementation on glycaemic control in adults with type 2 diabetes: two randomized controlled trials.

Kaja Falkenhain, Barbara F Oliveira, Hashim Islam, Helena Neudorf, Haoning H Cen, James D Johnson, Kenneth Madden, Joel Singer, Jeremy J Walsh, Jonathan P Little.

  Acute ingestion of the exogenous ketone monoester supplement [(R)-3-hydroxybutyl-(R)-3-hydroxybutyrate] lowers blood glucose, suggesting therapeutic potential in individuals with impaired glucose metabolism. However, it is unknown how acute or repeated ingestion of exogenous ketones affect blood glucose control in individuals with type 2 diabetes (T2D). We conducted two randomized, counter-balanced, double-blind, placebo-controlled crossover trials to determine if (1) acute exogenous ketone monoester (0.3 g/kg body mass; N=18), or (2) 14-day thrice daily pre-meal exogenous ketone monoester (15 g; N=15) supplementation could lower blood glucose in individuals living with T2D. A single dose of the ketone monoester supplement elevated blood ß-OHB to ~2 mM. There were no differences in the primary outcomes of plasma glucose concentration (acutely) or serum fructosamine (glycaemic control across 14 days) between conditions. Ketone monoester ingestion acutely increased insulin and lowered non-esterified fatty acid concentrations; plasma metabolomics confirmed a reduction in multiple free fatty acids species and select gluconeogenic amino acids. In contrast, no changes were observed in fasting metabolic outcomes following 14 days of supplementation. In the context of these randomized controlled trials, acute or repeated ketone monoester ingestion in adults with T2D did not lower blood glucose when consumed acutely in a fasted state, and did not improve glycaemic control following thrice daily pre-meal ingestion across 14 days. Future studies exploring the mechanistic basis for the (lack of) glucose-lowering effect of exogenous ketone supplementation in T2D and other populations are warranted.

Keywords:  glucose control; glycaemia; ketosis; metabolism; type 2 diabetes

DOI:  https://doi.org/10.1152/ajpendo.00332.2023
Lipids. 2023 Nov 24.

Dietary triacetin, but not medium chain triacylglycerides, blunts weight gain in diet-induced rat model of obesity.

Giulia Cisbani, Raphaël Chouinard-Watkins, Mackenzie E Smith, Arezou Malekanian, Rodrigo Valenzuela, Adam H Metherel, Richard P Bazinet.

  Consumption of a Western diet (WD) is known to increase the risk of obesity. Short or medium chain fatty acids influence energy metabolism, and triacetin, a synthetic short chain triacylglyceride, has been shown to lower body fat under normal conditions. This study aimed to investigate if triacetin as part of a WD modifies rat weight and body fat. Male rats were fed a control diet or WD for 8 weeks. At week 8, rats in the WD group were maintained on a WD diet or switched to a WD diet containing 30% energy from medium-chain triacylglyceride (WD-MCT) or triacetin (WD-T) for another 8 weeks. At week 16, rats were euthanized and liver, adipose and blood were collected. Tissue fatty acids (FAs) were quantified by gas chromatography (GC) and hepatic FAs were measured by GC-combustion-isotope ratio mass spectrometry for δ13 C-palmitic acid (PAM)-a novel marker of de novo lipogenesis (DNL). Rats fed WD-T had a body weight not statistically different to the control group, and gained less body weight than rats fed WD alone. Furthermore, WD-T fed rats had a lower fat mass, and lower total liver and plasma FAs compared to the WD group. Rats fed WD-T did not differ from WD in blood ketone or glucose levels, however, had a significantly lower hepatic δ13 C-PAM value than WD fed rats; suggestive of lower DNL. In summary, we show that triacetin has the potential to blunt weight gain and adipose tissue accumulation in a rodent model of obesity, possibly due to a decrease in DNL.

Keywords:  Western diet; body fat; medium chain triacylglycerides; obesity; triacetin; weight gain

DOI:  https://doi.org/10.1002/lipd.12381
bioRxiv. 2023 Nov 11. pii: 2023.11.10.566606. [Epub ahead of print]

The mitochondrial calcium uniporter is necessary for synaptic plasticity and proper mitochondrial morphology and distribution in the distal dendrites of CA2 neurons.

Katy E Pannoni, Quentin S Fischer, Renesa Tarannum, Mikel L Cawley, Mayd M Alsalman, Nicole Acosta, Chisom Ezigbo, Daniela V Gil, Logan A Campbell, Shannon Farris.

Mitochondria are dynamic organelles that are morphologically and functionally diverse across different cell types and subcellular compartments in order to meet unique energy demands. In neurons, mitochondria are critical to support synapses and synaptic plasticity. However, the mechanisms regulating mitochondria in synaptic plasticity are largely unknown. The mitochondrial calcium uniporter (MCU) regulates calcium entry into the mitochondria, which in turn regulates the bioenergetics and distribution of mitochondria to active synapses. Evidence suggests that calcium influx via MCU couples neuronal activity to mitochondrial metabolism and ATP production, which would allow neurons to rapidly adapt to changing energy demands. Intriguingly, MCU is uniquely enriched in CA2 distal dendrites relative to neighboring CA1 or CA3 distal dendrites, suggesting mitochondria there are molecularly distinct. However, the functional significance of this enrichment is not clear. Synapses onto CA2 distal dendrites, unlike synapses onto CA2 proximal dendrites, readily undergo long-term potentiation (LTP), but the mechanisms underlying the different plasticity profiles are unknown. Therefore, we investigated the role of MCU in regulating dendritic mitochondria and synaptic plasticity in CA2 distal dendrites. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU is required for LTP at CA2 distal dendrite synapses. Loss of LTP correlated with a trend for decreased spine density in CA2 distal dendrites of cKO mice compared to control (CTL) mice, which was predominantly seen in immature spines Moreover, mitochondria were significantly smaller and more numerous across all dendritic layers of CA2 in cKO mice compared to CTL mice, suggesting an overall increase in mitochondrial fragmentation. Fragmented mitochondria might have functional changes, such as altered ATP production, that might explain a deficit in synaptic plasticity. Collectively, our data reveal that MCU regulates layer-specific forms of plasticity in CA2 dendrites, potentially by maintaining proper mitochondria morphology and distribution within dendrites. Differences in MCU expression across different cell types and circuits might be a general mechanism to tune the sensitivity of mitochondria to cytoplasmic calcium levels to power synaptic plasticity.MAIN TAKE HOME POINTS: The mitochondrial calcium uniporter regulates plasticity selectively at synapses in CA2 distal dendrites.The MCU-cKO induced LTP deficit at synapses in CA2 distal dendrites correlates with a trending reduction in spine density.Loss of MCU in CA2 results in ultrastructural changes in dendritic mitochondria that suggest an increase in mitochondrial fragmentation. These ultrastructural changes could result in functional consequences, such as decreased ATP production, that could underlie the plasticity deficit.

DOI: https://doi.org/10.1101/2023.11.10.566606
medRxiv. 2023 Nov 09. pii: 2023.11.08.23298271. [Epub ahead of print]

Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA).

Philip A Kramer, Paul M Coen, Peggy M Cawthon, Giovanna Distefano, Steven R Cummings, Bret H Goodpaster, Russell T Hepple, Stephen B Kritchevsky, Eric G Shankland, David J Marcinek, Frederico G S Toledo, Kate A Duchowny, Sofhia V Ramos, Stephanie Harrison, Anne B Newman, Anthony J A Molina.

The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70-94 years). A Short Physical Performance Battery score ≤ 8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (e.g. Maximal Complex I&II OXPHOS: Women=55.06 +/- 15.95; Men=65.80 +/- 19.74; p<0.001) and in individuals with mobility impairment compared to those without (e.g., Maximal Complex I&II OXPHOS in women: SPPB≥9=56.59 +/- 16.22; SPPB≤8=47.37 +/- 11.85; p<0.001). Muscle energetics were negatively associated with age only in men (e.g., Maximal ETS capacity: R=-0.15, p=0.02; age/sex interaction, p=0.04), resulting in muscle energetics measures that were significantly lower in women than men in the 70-79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70-79 age group (70-79 age group, OR age-adjusted =1.78, 95% CI=1.03, 3.08, p=0.038; 80+ age group, OR age-adjusted =1.05, 95% CI=0.52, 2.15, p=0.89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment.

DOI: https://doi.org/10.1101/2023.11.08.23298271
Biology (Basel). 2023 Nov 19. pii: 1450. [Epub ahead of print]12(11):

The Molecular Mechanisms of Fuel Utilization during Exercise.

Anna Pi, Sneha Damal Villivalam, Sona Kang.

  Exercise is widely recognized for its positive impact on human health and well-being. The process of utilizing substrates in skeletal muscle during exercise is intricate and governed by complex mechanisms. Carbohydrates and lipids serve as the primary fuel sources for skeletal muscle during exercise. It is now understood that fuel selection during exercise is not solely determined by physical activity itself but is also influenced by the overall metabolic state of the body. The balance between lipid and carbohydrate utilization significantly affects exercise capacity, including endurance, fatigue, and overall performance. Therefore, comprehensively understanding the regulation of substrate utilization during exercise is of utmost importance. The aim of this review is to provide an extensive overview of the current knowledge regarding the pathways involved in the regulation of substrate utilization during exercise. By synthesizing existing research, we can gain a holistic perspective on the intricate relationship between exercise, metabolism, and fuel selection. This advanced understanding has the potential to drive advancements in the field of exercise science and contribute to the development of personalized exercise strategies for individuals looking to optimize their performance and overall health.

Keywords:  exercise; fuel utilization; skeletal muscle

DOI:  https://doi.org/10.3390/biology12111450
J Cachexia Sarcopenia Muscle. 2023 Nov 20.

MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism.

Shu Yang, Guangyan Yang, Xinyu Wang, Lixing Li, Yanchun Li, Jiaqing Xiang, Lin Kang, Zhen Liang.

  BACKGROUND: Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR-92b on the upregulation of exercise training-induced physical performance.METHODS: Adeno-associated virus (AAV)-mediated skeletal muscle miR-92b overexpression in C57BLKS/J mice, and global knockout of miR-92b mice were used to explore the function of miR-92b in glycogen and lactate metabolism in skeletal muscle. AAV-mediated UGP2 or MCT4 knockdown in WT or miR-92 knockout mice was used to confirm whether miR-92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass-related and function-related proteins were analysed by immunoblotting or immunostaining.
RESULTS: Global knockout of miR-92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs. 1.043 ± 0.040, **P = 0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs. 3.207 ± 0.2511, *P = 0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs. 4231 ± 90.29, ***P = 0.0006; running time to exhaustion, 186.8 ± 8.027 vs. 220.8 ± 3.156, **P = 0.0028), as compared with those observed in the control mice. Mice skeletal muscle overexpressing miR-92b (both miR-92b-3p and miR-92b-5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs. 0.535 ± 0.0194, **P = 0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs. 5.467 ± 0.1892, *P = 0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs. 3228 ± 149.8, ***P<0.0001; running time to exhaustion, 225.5 ± 7.689 vs. 163 ± 6.476, **P = 0.001). Mechanistic analysis revealed that miR-92b-3p targets UDP-glucose pyrophosphorylase 2 (UGP2) expression to inhibit glycogen synthesis, while miR-92b-5p represses lactate extrusion by directly target monocarboxylate transporter 4 (MCT4). Knockdown of UGP2 and MCT4 reversed the effects observed in the absence of miR-92b in vivo.
CONCLUSIONS: This study revealed regulatory pathways, including miR-92b-3p/UGP2/glycogen synthesis and miR-92b-5p/MCT4/lactate extrusion, which could be targeted to control exercise capacity.

Keywords:  Exercise capacity; Glycogen synthesis; Lactate extrusion; Skeletal muscle; miR-92b

DOI:  https://doi.org/10.1002/jcsm.13377
Clin Sci (Lond). 2023 Nov 29. 137(22): 1721-1751

Hallmarks of ageing in human skeletal muscle and implications for understanding the pathophysiology of sarcopenia in women and men.

Antoneta Granic, Karen Suetterlin, Tea Shavlakadze, Miranda D Grounds, Avan A Sayer.

  Ageing is a complex biological process associated with increased morbidity and mortality. Nine classic, interdependent hallmarks of ageing have been proposed involving genetic and biochemical pathways that collectively influence ageing trajectories and susceptibility to pathology in humans. Ageing skeletal muscle undergoes profound morphological and physiological changes associated with loss of strength, mass, and function, a condition known as sarcopenia. The aetiology of sarcopenia is complex and whilst research in this area is growing rapidly, there is a relative paucity of human studies, particularly in older women. Here, we evaluate how the nine classic hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication contribute to skeletal muscle ageing and the pathophysiology of sarcopenia. We also highlight five novel hallmarks of particular significance to skeletal muscle ageing: inflammation, neural dysfunction, extracellular matrix dysfunction, reduced vascular perfusion, and ionic dyshomeostasis, and discuss how the classic and novel hallmarks are interconnected. Their clinical relevance and translational potential are also considered.

Keywords:  hallmarks of ageing; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1042/CS20230319