bims-kimdis 2023-12-31 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒12‒31
nineteen papers selected by
Matías Javier Monsalves Álvarez

Nutrition and dietary restrictions in cancer prevention.
Effect of Acute and Chronic Ingestion of Exogenous Ketone Supplements on Blood Pressure: A Systematic Review and Meta-Analysis.
Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA).
Molecular profiling of high-level athlete skeletal muscle after acute endurance or resistance exercise - a systems biology approach.
Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.
The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity.
Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes.
Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.
Inhaled salbutamol induces leanness in well-trained healthy females but not males during a period of endurance training: a randomised controlled trial.
Short-chain fatty acids (SCFAs) from gastrointestinal disorders, metabolism, epigenetics, central nervous system to cancer - A mini-review.
Low-Carbohydrate Diet Macronutrient Quality and Weight Change.
Metabolic Communication by SGLT2 Inhibition.
Association of skeletal muscle oxidative capacity with muscle function, sarcopenia-related exercise performance, and intramuscular adipose tissue in older adults.
The role of mitochondrial dynamics in disease.
The muscle stem cell niche at a glance.
Fat oxidation rates and cardiorespiratory responses during exercise in different subject populations with post-acute sequelae of SARS-CoV-2 infection: a comparison with normative percentile values.
Autologous mitochondrial transplantation in male mice as a strategy to prevent deleterious effects of peripheral ischemia-reperfusion.
Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD.
Impact of fasting on the AMPK and PGC-1α axis in rodent and human skeletal muscle: A systematic review.

Biochim Biophys Acta Rev Cancer. 2023 Dec 24. pii: S0304-419X(23)00212-3. [Epub ahead of print] 189063

Nutrition and dietary restrictions in cancer prevention.

Amrendra Mishra, Giacomo Giuliani, Valter D Longo.

  The composition and pattern of dietary intake have emerged as key factors influencing aging, regeneration, and consequently, healthspan and lifespan. Cancer is one of the major diseases more tightly linked with aging, and age-related mortality. Although the role of nutrition in cancer incidence is generally well established, we are far from a consensus on how diet influences tumour development in different tissues. In this review, we will discuss how diet and dietary restrictions affect cancer risk and the molecular mechanisms potentially responsible for their effects. We will cover calorie restriction, intermittent fasting, prolonged fasting, fasting-mimicking diet, time-restricted eating, ketogenic diet, high protein diet, Mediterranean diet, and the vegan and vegetarian diets.

Keywords:  Calorie restriction; Cancer prevention; Dietary restrictions; Fasting mimicking diet; Intermittent fasting; Mediterranean diet

DOI:  https://doi.org/10.1016/j.bbcan.2023.189063
J Diet Suppl. 2023 Dec 25. 1-19

Effect of Acute and Chronic Ingestion of Exogenous Ketone Supplements on Blood Pressure: A Systematic Review and Meta-Analysis.

Alexis Marcotte-Chénard, Renaud Tremblay, Kaja Falkenhain, Jonathan P Little, Eléonor Riesco.

  Exogenous ketone supplements have been suggested to have potential cardiovascular benefits, but their overall effect on blood pressure is unclear. Our objective was to perform a systematic review and meta-analysis on the effects of exogenous ketone supplements on blood pressure (BP) and concomitant changes in resting heart rate (HR). Five databases were searched on January 27th, 2023, for randomized and non-randomized studies. A random-effects model meta-analysis was performed including all studies jointly and separately for acute and chronic ingestion of ketone supplements. Out of 4012 studies identified in the search, 4 acute and 6 chronic studies with n = 187 participants were included. Pooled results (n = 10) showed no change in systolic (SMD [95% CI]= -0.14 [-0.40; 0.11]; I2= 30%; p = 0.17) or diastolic BP (-0.12 [-0.30; 0.05]; I2= 0%; p = 0.69), with a potential tendency observed toward increased resting heart rate (0.17 [-0.14; 0.47]; I2= 40%; p = 0.10). Similar results for systolic and diastolic BP were observed when assessing separately the effect of acute and chronic ingestion of ketone supplements (p ≥ 0.33). Supplement dosage was found to modulate the increase in resting heart rate (0.019 ± 0.006; p = 0.013; R2=100%), suggesting that higher supplement doses lead to a higher resting heart rate. Based on currently available data, acute or prolonged ingestion of ketone supplements does not seem to modulate BP. However, a tendency for HR to increase after acute ingestion was observed, particularly with higher doses. Higher quality studies with appropriate standardized measurements are needed to confirm these results.

Keywords:  BHB; Vascular function; hemodynamic response; ketosis; β-OHB; β-hydroxybutyrate

DOI:  https://doi.org/10.1080/19390211.2023.2289961
J Gerontol A Biol Sci Med Sci. 2023 Dec 27. pii: glad283. [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, ORage-adjusted=1.78, 95% CI=1.03, 3.08, p=0.038; 80+ age group, ORage-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.

Keywords:  Mitochondria; bioenergetics; disability; gender; lower-extremity

DOI:  https://doi.org/10.1093/gerona/glad283
Mol Metab. 2023 Dec 21. pii: S2212-8778(23)00191-6. [Epub ahead of print] 101857

Molecular profiling of high-level athlete skeletal muscle after acute endurance or resistance exercise - a systems biology approach.

Stefan M Reitzner, Eric B Emanuelsson, Muhammad Arif, Bogumil Kaczkowski, Andrew Tj Kwon, Adil Mardinoglu, Erik Arner, Mark A Chapman, Carl Johan Sundberg.

  OBJECTIVE: Long-term high-level exercise training leads to improvements in physical performance and multi-tissue adaptation following changes in molecular pathways. While skeletal muscle baseline differences between exercise-trained and untrained individuals have been previously investigated, it remains unclear how training history influences human multi-omics responses to acute exercise.METHODS: We recruited and extensively characterized 24 individuals categorized as endurance athletes with >15 years of training history, strength athletes or control subjects. Timeseries skeletal muscle biopsies were taken from M. vastus lateralis at three time-points after endurance or resistance exercise was performed and multi-omics molecular analysis performed.
RESULTS: Our analyses revealed distinct activation differences of molecular processes such as fatty- and amino acid metabolism and transcription factors such as HIF1A and the MYF-family. We show that endurance athletes have an increased abundance of carnitine-derivates while strength athletes increase specific phospholipid metabolites compared to control subjects. Additionally, for the first time, we show the metabolite sorbitol to be substantially increased with acute exercise. On transcriptional level, we show that acute resistance exercise stimulates more gene expression than acute endurance exercise. This follows a specific pattern, with endurance athletes uniquely down-regulating pathways related to mitochondria, translation and ribosomes. Finally, both forms of exercise training specialize in diverging transcriptional directions, differentiating themselves from the transcriptome of the untrained control group.
CONCLUSIONS: We identify a "transcriptional specialization effect" by transcriptional narrowing and intensification, and molecular specialization effects on metabolomic level Additionally, we performed multi-omics network and cluster analysis, providing a novel resource of skeletal muscle transcriptomic and metabolomic profiling in highly trained and untrained individuals.

Keywords:  athletes; human; metabolomics; molecular exercise effects; multi-omics; systems biology

DOI:  https://doi.org/10.1016/j.molmet.2023.101857
Elife. 2023 Dec 27. pii: RP87340. [Epub ahead of print]12

Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.

Alexis Diaz-Vegas, Søren Madsen, Kristen C Cooke, Luke Carroll, Jasmine X Y Khor, Nigel Turner, Xin Y Lim, Miro A Astore, Jonathan C Morris, Anthony S Don, Amanda Garfield, Simona Zarini, Karin A Zemski Berry, Andrew P Ryan, Bryan C Bergman, Joseph T Brozinick, David E James, James G Burchfield.

  Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Keywords:  biochemistry; cell biology; ceramides; chemical biology; coenzyme Q; human; insulin resistance; mitochondria; mouse; muscle; rat

DOI:  https://doi.org/10.7554/eLife.87340
Immunol Rev. 2023 Dec 25.

The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity.

Christopher D Putnam, Lori Broderick, Hal M Hoffman.

  From studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease. We have seen cohesion in results from clinical studies in CAPS patients, ex vivo studies of human cells and murine cells, and in vivo murine models leading to our understanding of the downstream pathways, cytokine secretion, and cell death pathways that has solidified the role of autoinflammation in the pathogenesis of human disease. Recent advances in our understanding of the structure of the inflammasome have provided ways for us to visualize normal and mutant protein function and pharmacologic inhibition. The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein.

Keywords:  NLRP3; cryopyrin-associated periodic syndrome; familial cold autoinflammatory syndrome; inflammasome

DOI:  https://doi.org/10.1111/imr.13292
Curr Atheroscler Rep. 2023 Dec 27.

Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes.

Jingjing Zhu, John P H Wilding.

  PURPOSE OF REVIEW: To highlight that body fat depletion (the Yin paradigm) with glucose-lowering treatments (the Yang paradigm) are associated with metabolic benefits for patients with type 2 diabetes mellitus (T2DM).RECENT FINDINGS: The sodium-glucose cotransporter-2 inhibitor-mediated sodium/glucose deprivation can directly improve glycemic control and kidney outcome in patients with T2DM. The glucose deprivation might also promote systemic fatty acid β-oxidation to deplete ectopic/visceral fat and thereby contribute to the prevention of cardiovascular diseases. As with metabolic surgery, bioengineered incretin-based medications with potent anorexigenic and insulinotropic efficacy can significantly reduce blood glucose as well as body weight (especially in the ectopic/visceral fat depots). The latter effects could be a key contributor to their cardiovascular-renal protective effects. In addition to a healthy diet, the newer glucose-lowering medications, with body fat reduction effects, should be prioritized when treating patients with T2DM, especially for those with established cardiovascular/renal risks or diseases.

Keywords:  Body fat; Incretin; Metabolic benefit; Sodium-glucose cotransporter-2 inhibitor; Type 2 diabetes

DOI:  https://doi.org/10.1007/s11883-023-01181-4
Front Mol Biosci. 2023 ;10 1336416

Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.

Donato D'Angelo, Denis Vecellio Reane, Anna Raffaello.

  Ca2+ ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca2+ homeostasis since mitochondrial Ca2+ (mitCa2+) is a key regulator of oxidative metabolism and cell death. MitCa2+ uptake is mediated by the mitochondrial Ca2+ uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa2+ uptake stimulates the activity of three key enzymes of the Krebs cycle, thereby modulating ATP production and promoting oxidative metabolism. As Paracelsus stated, "Dosis sola facit venenum,"in pathological conditions, mitCa2+ overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa2+ accumulation is also associated with a pathological increase of reactive oxygen species (ROS). In this article, we review the precise regulation and the effectors of mitCa2+ in physiopathological processes.

Keywords:  calcium; cell death; metabolism; mitochondria; mitochondrial calcium uniporter (MCU)

DOI:  https://doi.org/10.3389/fmolb.2023.1336416
ERJ Open Res. 2023 Nov;pii: 00657-2023. [Epub ahead of print]9(6):

Inhaled salbutamol induces leanness in well-trained healthy females but not males during a period of endurance training: a randomised controlled trial.

Morten Hostrup, Cecilie Weinreich, Mathias Bjerre, Dario Kohlbrenner, Jens Bangsbo, Søren Jessen.

Introduction: Many athletes use short-acting inhaled β2-agonists multiple times weekly during training sessions to prevent exercise-induced bronchoconstriction, but it is unclear if treatment impairs training outcomes. Herein, we investigated performance adaptations in well-trained females and males training with prior inhalation of salbutamol.Methods: 19 females and 21 males with maximal oxygen uptake (V'O2max) of 50.5±3.3 and 57.9±4.9 mL·min-1·kg-1, respectively, participated in this double-blinded, placebo-controlled, parallel-group study. We randomised participants to placebo or salbutamol inhalation (800-1600 µg·training day-1) for 6 weeks of combined endurance (1× per week) and high-intensity interval training (2× per week). We assessed participants' body composition, V'O2max and muscle contractile function, and collected vastus lateralis muscle biopsies.
Results: Salbutamol induced a sex-specific loss of whole-body fat mass (sex×treatment: p=0.048) where only salbutamol-treated females had a fat mass reduction compared to placebo (-0.8 kg at 6 weeks; 95% CI: -0.5 to -1.6; p=0.039). Furthermore, salbutamol-treated females exhibited a repartitioning effect, lowering fat mass while gaining lean mass (p=0.011), which was not apparent for males (p=0.303). Salbutamol negatively impacted V'O2max in both sexes (treatment main effect: p=0.014) due to a blunted increase in V'O2max during the initial 4 weeks of the intervention. Quadriceps contractile strength was impaired in salbutamol-treated females (-39 N·m; 95% CI: -61 to -17; p=0.002) compared to placebo at 6 weeks. Muscle electron transport chain complex I-V abundance increased with salbutamol (treatment main effect: p=0.035), while content of SERCAI, β2-adrenoceptor and desmin remained unchanged.
Conclusion: Inhaled salbutamol appears to be an effective repartitioning agent in females but may impair aerobic and strength-related training outcomes.

DOI: https://doi.org/10.1183/23120541.00657-2023
Chem Biol Interact. 2023 Dec 23. pii: S0009-2797(23)00518-5. [Epub ahead of print] 110851

Short-chain fatty acids (SCFAs) from gastrointestinal disorders, metabolism, epigenetics, central nervous system to cancer - A mini-review.

Khalid A Abdelhalim.

  Short-chain fatty acids (SCFAs), generated through microbial fermentation of dietary fibers and proteins in the gut, play a pivotal role in maintaining intestinal integrity, cellular function, and the immune response. SCFAs, including butyrate, acetate, and propionate, are absorbed in the colon or excreted through feces, contributing to essential physiological processes. Butyrate, a primary energy source for colonocytes, exhibits anti-inflammatory properties and regulates key pathways, such as nuclear factor-κB (NF-κB) inhibition. SCFAs' impact extends beyond the intestines, influencing the gut-brain axis, systemic circulation, and folate metabolism. A decline in colonic SCFAs has been linked to gastrointestinal diseases, emphasizing their clinical relevance, while their effects on immune checkpoints, such as ipilimumab, provide intriguing prospects for cancer therapy. This mini-review explores SCFAs' diverse roles, shedding light on their significance in health and potential implications for disease management. Understanding SCFAs' intricate mechanisms enhances our knowledge of their therapeutic potential and highlights their emerging importance in various physiological contexts.

Keywords:  Cancer; Central nervous system; Folate; Inflammation; Microbial metabolites; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.cbi.2023.110851
JAMA Netw Open. 2023 Dec 01. 6(12): e2349552

Low-Carbohydrate Diet Macronutrient Quality and Weight Change.

Binkai Liu, Yang Hu, Sharan K Rai, Molin Wang, Frank B Hu, Qi Sun.

Importance: The associations of low-carbohydrate diets (LCDs) with long-term weight management remains unclear, and the source and quality of macronutrients within LCDs are less explored.Objectives: To prospectively examine associations between changes in LCD indices and weight change among US adults.
Design, Setting, and Participants: This prospective cohort study included initially healthy participants at baseline from the Nurses' Health Study (NHS; 1986-2010), Nurses' Health Study II (NHSII; 1991-2015), and Health Professionals Follow-up Study (HPFS; 1986-2018). Data analysis was performed between November 2022 and April 2023.
Exposures: Five LCD indices were examined: (1) a total LCD (TLCD) emphasizing overall lower carbohydrate intake; (2) an animal-based LCD (ALCD) that emphasized animal-sourced protein and fat; (3) a vegetable-based LCD (VLCD) that emphasized plant-sourced protein and fat; (4) a healthy LCD (HLCD) emphasizing less refined carbohydrates, more plant protein, and healthy fat; and (5) an unhealthy LCD (ULCD) emphasizing less healthful carbohydrates, more animal protein, and unhealthy fat.
Main Outcomes and Measures: The outcome of interest was 4-year changes in self-reported body weight.
Results: A total of 123 332 participants (mean [SD] age, 45.0 [9.7] years; 103 320 [83.8%] female) were included in this study. The median carbohydrate intake (as a percentage of energy) of the highest quintiles of TLCD score at baseline ranged from 38.3% in HPFS to 40.9% in NHSII. Mean weight gain over 4-year intervals among participants varied from 0.8 kg in the HPFS to 1.8 kg in the NHSII. After adjusting for demographics and baseline and concomitant changes of selected lifestyle factors, each 1-SD increase in TLCD score was associated with 0.06 (95% CI, 0.04-0.08) kg more weight gain over the 4-year periods. Similarly, participants gained 0.13 (95% CI, 0.11 to 0.14) kg per each 1-SD increase in ALCD score and 0.39 (95% CI, 0.37 to 0.40) kg per each 1-SD change in ULCD score. In contrast, each 1-SD increase in VLCD score was associated with 0.03 (95% CI, 0.01 to 0.04) kg less weight gain, and each 1-SD increase in HLCD score was associated with 0.36 (95% CI, 0.35 to 0.38) kg less weight gain. The associations were more pronounced among obese individuals (per 1-SD increase in HLCD score: BMI ≥30, 0.88 [95% CI, 0.80, 0.97] kg less weight gain; BMI <25, 0.23 [95% CI, 0.20, 0.26] kg less weight gain; P for interaction < .001).
Conclusions and Relevance: These findings suggest that the quality of LCDs may play a critical role in modulating long-term weight change. Only LCDs that emphasized high-quality protein, fat, and carbohydrates from whole grains and other plant-based foods were associated with less weight gain.

DOI: https://doi.org/10.1001/jamanetworkopen.2023.49552
Circulation. 2023 Dec 28.

Metabolic Communication by SGLT2 Inhibition.

Anja M Billing, Young Chul Kim, Søren Gullaksen, Benedikt Schrage, Janice Raabe, Arvid Hutzfeldt, Fatih Demir, Elina Kovalenko, Moritz Lassé, Aurelien Dugourd, Robin Fallegger, Birgit Klampe, Johannes Jaegers, Qing Li, Olha Kravtsova, Maria Crespo-Masip, Amelia Palermo, Robert A Fenton, Elion Hoxha, Stefan Blankenberg, Paulus Kirchhof, Tobias B Huber, Esben Laugesen, Tanja Zeller, Maria Chrysopolou, Julio Saez-Rodriguez, Christina Magnussen, Thomas Eschenhagen, Alexander Staruschenko, Gary Siuzdak, Per L Poulsen, Clarissa Schwab, Friederike Cuello, Volker Vallon, Markus M Rinschen.

  BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood.METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia.
RESULTS: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell-engineered heart tissue.
CONCLUSION: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.

Keywords:  diabetes mellitus; gastrointestinal microbiome; heart; kidney; metabolome; plasma; proteome; sodium-glucose transporter 2 inhibitors; uremic toxins; urine

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.065517
Geroscience. 2023 Dec 28.

Association of skeletal muscle oxidative capacity with muscle function, sarcopenia-related exercise performance, and intramuscular adipose tissue in older adults.

Akito Yoshiko, Kana Shiozawa, Shiori Niwa, Hideyuki Takahashi, Teruhiko Koike, Kohei Watanabe, Keisho Katayama, Hiroshi Akima.

  Muscle function and exercise performance measures, such as muscle endurance capacity, maximal strength, chair stand score, gait speed, and Timed Up and Go score, are evaluated to diagnose sarcopenia and frailty in older individuals. Furthermore, intramuscular adipose tissue (IntraMAT) content increases with age. Skeletal muscle oxidative capacity determines muscle metabolism and maintains muscle performance. This study aimed to investigate the association of skeletal muscle oxidative capacity with muscle function, exercise performance, and IntraMAT content in older individuals. Thirteen older men and women participated in this study. Skeletal muscle oxidative capacity was assessed by the recovery speed of muscle oxygen saturation after exercise using near-infrared spectroscopy from the medial gastrocnemius. We assessed two muscle functions, peak torque and time to task failure, and four sarcopenia-related exercise performances: handgrip strength, gait speed, 30-s chair stand, and Timed Up and Go. The IntraMAT content was measured using axial magnetic resonance imaging. The results showed a relationship between skeletal muscle oxidative capacity and gait speed but not with muscle functions and other exercise performance measures. Skeletal muscle oxidative capacity was not related to IntraMAT content. Skeletal muscle oxidative capacity, which may be indicative of the capacity of muscle energy production in the mitochondria, is related to locomotive functions but not to other functional parameters or skeletal fat infiltration.

Keywords:  Intramuscular adipose tissue; Muscle endurance function; Muscle oxidative capacity; Physical dysfunction

DOI:  https://doi.org/10.1007/s11357-023-01043-6
MedComm (2020). 2023 Dec;4(6): e462

The role of mitochondrial dynamics in disease.

Yujuan Wang, Xinyan Dai, Hui Li, Huiling Jiang, Junfu Zhou, Shiying Zhang, Jiacheng Guo, Lidu Shen, Huantao Yang, Jie Lin, Hengxiu Yan.

  Mitochondria are multifaceted and dynamic organelles regulating various important cellular processes from signal transduction to determining cell fate. As dynamic properties of mitochondria, fusion and fission accompanied with mitophagy, undergo constant changes in number and morphology to sustain mitochondrial homeostasis in response to cell context changes. Thus, the dysregulation of mitochondrial dynamics and mitophagy is unsurprisingly related with various diseases, but the unclear underlying mechanism hinders their clinical application. In this review, we summarize the recent developments in the molecular mechanism of mitochondrial dynamics and mitophagy, particularly the different roles of key components in mitochondrial dynamics in different context. We also summarize the roles of mitochondrial dynamics and target treatment in diseases related to the cardiovascular system, nervous system, respiratory system, and tumor cell metabolism demanding high-energy. In these diseases, it is common that excessive mitochondrial fission is dominant and accompanied by impaired fusion and mitophagy. But there have been many conflicting findings about them recently, which are specifically highlighted in this view. We look forward that these findings will help broaden our understanding of the roles of the mitochondrial dynamics in diseases and will be beneficial to the discovery of novel selective therapeutic targets.

Keywords:  context; disease; mitochondrial dynamics; mitophagy; target treatment

DOI:  https://doi.org/10.1002/mco2.462
J Cell Sci. 2023 Dec 15. pii: jcs261200. [Epub ahead of print]136(24):

The muscle stem cell niche at a glance.

Margaret Hung, Hsiao-Fan Lo, Grace E L Jones, Robert S Krauss.

  Skeletal muscle stem cells (MuSCs, also called satellite cells) are the source of the robust regenerative capability of this tissue. The hallmark property of MuSCs at homeostasis is quiescence, a reversible state of cell cycle arrest required for long-term preservation of the stem cell population. MuSCs reside between an individual myofiber and an enwrapping basal lamina, defining the immediate MuSC niche. Additional cell types outside the basal lamina, in the interstitial space, also contribute to niche function. Quiescence is actively maintained by multiple niche-derived signals, including adhesion molecules presented from the myofiber surface and basal lamina, as well as soluble signaling factors produced by myofibers and interstitial cell types. In this Cell Science at a Glance article and accompanying poster, we present the most recent information on how niche signals promote MuSC quiescence and provide perspectives for further research.

Keywords:  Cell adhesion; Cell signaling; Muscle; Muscle stem cell; Quiescence; Stem cell niche

DOI:  https://doi.org/10.1242/jcs.261200
Front Physiol. 2023 ;14 1310319

Fat oxidation rates and cardiorespiratory responses during exercise in different subject populations with post-acute sequelae of SARS-CoV-2 infection: a comparison with normative percentile values.

Andrea Meloni, Roberto Codella, Daniel Gotti, Simone Di Gennaro, Livio Luzi, Luca Filipas.

  Introduction: Post-acute sequelae of SARS-CoV-2 infection (PASC) presents a spectrum of symptoms following acute COVID-19, with exercise intolerance being a prevalent manifestation likely linked to disrupted oxygen metabolism and mitochondrial function. This study aims to assess maximal fat oxidation (MFO) and exercise intensity at MFO (FATmax) in distinct PASC subject groups and compare these findings with normative data. Methods: Eight male subjects with PASC were involved in this study. The participants were divided into two groups: "endurance-trained" subjects (V˙O2max > 55 mL/min/kg) and "recreationally active" subjects (V˙O2max < 55 mL/min/kg). Each subject performed a graded exercise test until maximal oxygen consumption (V˙O2max) to measure fat oxidation. Subsequently, MFO was assessed, and FATmax was calculated as the ratio between V˙O2 at MFO and V˙O2 max. Results: The MFO and FATmax of "endurance-trained" subjects were 0.85, 0.89, 0.71, and 0.42 and 68%, 69%, 64%, and 53%, respectively. Three out of four subjects showed both MFO and FATmax values placed over the 80th percentile of normative data. The MFO and FATmax of "recreationally active" subjects were 0.34, 0.27, 0.35, and 0.38 and 47%, 39%, 43%, and 41%, respectively. All MFO and FATmax values of those subjects placed below the 20th percentile or between the 20th and 40th percentile. Discussion: Significant differences in MFO and FATmax values between 'endurance-trained' and "recreationally active" subjects suggest that specific endurance training, rather than simply an active lifestyle, may provide protective effects against alterations in mitochondrial function during exercise in subjects with PASC.

Keywords:  cycling; exercise performance; fat oxidation; metabolic dysfunction; post-acute sequelae of SARS-CoV-2 infection

DOI:  https://doi.org/10.3389/fphys.2023.1310319
Am J Physiol Cell Physiol. 2023 Dec 25.

Autologous mitochondrial transplantation in male mice as a strategy to prevent deleterious effects of peripheral ischemia-reperfusion.

Lauréline Boutonnet, Joris Mallard, Anne-Laure Charles, Elyse Hucteau, Bernard Geny, Anne Lejay, Antoine Grandperrin.

  Background and objective: Ischemia-reperfusion (IR) is known to induce severe tissue damage, notably through mitochondrial dysfunction. Mitochondrial transplantation has emerged as a promising therapeutic strategy in cardiac IR, however few studies have previously assessed its efficacy in the context of peripheral IR. Therefore, the objective of this study was to assess the effect of mitochondrial transplantation in a hindlimb model of IR injury. Methods: Thirty-six SWISS mice were divided into three groups: control (CTL, n=12), ischemia-reperfusion (IR, n=12) and IR with mitochondrial transplantation (MT, n=12). Ischemia (2 hours) was induced using the tourniquet model, around the right hind limb in IR and MT groups. In MT group, mitochondria isolated from the right rectus muscle, a non-ischemic region, were injected shortly before reperfusion. Mitochondrial respiration, calcium retention capacity and western blotting analysis were performed 2 hours after reperfusion. Results: Compared to CTL group, IR led to a decrease in the mitochondrial respiratory capacity, particularly for the basal state (-30%; p=0.015) and the oxidative phosphorylation (-36%; p=0.024), as well as calcium retention capacity (-45%; p=0.007). Interestingly, mitochondrial transplantation partially restored these functions since no difference between MT and CTL groups were found. Additionally, the administration of healthy mitochondria resulted in a positive regulation of redox balance and mitochondrial dynamics within the skeletal muscle. Conclusion: While further investigations are needed to better characterize underlying mechanisms, mitochondrial transplantation represents a promising strategy in the setting of IR-induced muscular damage.

Keywords:  Skeletal muscle; mPTP; mitochondrial dynamics; mitochondrial function; reactive oxygen species

DOI:  https://doi.org/10.1152/ajpcell.00639.2023
Metabolism. 2023 Dec 22. pii: S0026-0495(23)00369-4. [Epub ahead of print] 155765

Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD.

Juan Carlos Bórquez, Francisco Díaz-Castro, Francisco Pino-de La Fuente, Karla Espinoza, Ana María Figueroa, Inma Martínez-Ruíz, Vanessa Hernández, Iliana López-Soldado, Raúl Ventura, Joan Carles Domingo, Marta Bosch, Alba Fajardo, David Sebastian, Alejandra Espinosa, Albert Pol, Antonio Zorzano, Víctor Cortés, María Isabel Hernández-Alvarez, Rodrigo Troncoso.

  BACKGROUND AND AIM: The excessive accumulation of lipid droplets (LDs) is a defining characteristic of nonalcoholic fatty liver disease (NAFLD). The interaction between LDs and mitochondria is functionally important for lipid metabolism homeostasis. Exercise improves NAFLD, but it is not known if it has an effect on hepatic LD-mitochondria interactions. Here, we investigated the influence of exercise on LD-mitochondria interactions and its significance in the context of NAFLD.APPROACH AND RESULTS: Mice were fed high-fat diet (HFD) or HFD-0.1 % methionine and choline-deficient diet (MCD) to emulate simple hepatic steatosis or non-alcoholic steatohepatitis, respectively. In both models, aerobic exercise decreased the size of LDs bound to mitochondria and the number of LD-mitochondria contacts. Analysis showed that the effects of exercise on HOMA-IR and liver triglyceride levels were independent of changes in body weight, and a positive correlation was observed between the number of LD-mitochondria contacts and NAFLD severity and with the lipid droplet size bound to mitochondria. Cellular fractionation studies revealed that ATP-coupled respiration and fatty acid oxidation (FAO) were greater in hepatic peridroplet mitochondria (PDM) from HFD-fed exercised mice than from equivalent sedentary mice. Finally, exercise increased FAO and mitofusin-2 abundance exclusively in PDM through a mechanism involving the curvature of mitochondrial membranes and the abundance of saturated lipids. Accordingly, hepatic mitofusin-2 ablation prevented exercise-induced FAO in PDM.
CONCLUSIONS: This study demonstrates that aerobic exercise has beneficial effects in murine NAFLD models by lessening the interactions between hepatic LDs and mitochondria, and by decreasing LD size, correlating with a reduced severity of NAFLD. Additionally, aerobic exercise increases FAO in PDM and this process is reliant on Mfn-2 enrichment, which modifies LD-mitochondria communication.

Keywords:  Fatty acid oxidation; Hepatocytes; Mitofusin-2; Peridroplet mitochondria; Steatohepatitis

DOI:  https://doi.org/10.1016/j.metabol.2023.155765
Metabolism. 2023 Dec 26. pii: S0026-0495(23)00372-4. [Epub ahead of print] 155768

Impact of fasting on the AMPK and PGC-1α axis in rodent and human skeletal muscle: A systematic review.

K L Storoschuk, D Lesiuk, J Nuttall, M LeBouedec, A Khansari, H Islam, B J Gurd.

  Based primarily on evidence from rodent models fasting is currently believed to improve metabolic health in via activation of the AMPK-PGC-1α axis in skeletal muscle. However, it is unclear whether the skeletal muscle AMPK-PGC-1α axis is activated by fasting in humans. The current systematic review examined the fasting response in skeletal muscle from 34 selected studies (7 human, 21 mouse, and 6 rat). From these studies, we gathered 38 unique data points related to AMPK and 47 related to PGC-1α. In human studies, fasting mediated activation of the AMPK-PGC-1α axis is largely absent. Although evidence does support fasting-induced activation of the AMPK-PGC-1α axis in rodent skeletal muscle, the evidence is less robust than anticipated. Our findings question the ability of fasting to activate the AMPK-PGC-1α axis in human skeletal muscle and suggest that the metabolic benefits of fasting in humans are associated with caloric restriction rather than the induction of mitochondrial biogenesis. Registration: https://doi.org/10.17605/OSF.IO/KWNQY.

Keywords:  AMPK; Fasting; Mitochondrial biogenesis; PGC-1α

DOI:  https://doi.org/10.1016/j.metabol.2023.155768