bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024‒02‒25
eighteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Development and validation of a multiplexed LC-MS/MS ketone body assay for clinical diagnostics.
  2. Levels of Circulating Ketone Bodies in Patients Undergoing Cardiac Surgery on Cardiopulmonary Bypass.
  3. Relationship Between Serum β-Hydroxybutyrate and Hepatic Fatty Acid Oxidation in Individuals with Obesity and NAFLD.
  4. Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation.
  5. Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
  6. The Structure of the Cardiac Mitochondria Respirasome Is Adapted for the β-Oxidation of Fatty Acids.
  7. Lactate administration induces skeletal muscle synthesis by influencing Akt/mTOR and MuRF1 in non-trained mice but not in trained mice.
  8. Magnesium and the Hallmarks of Aging.
  9. Effect of Short-Chain Fatty Acids on Inflammatory and Metabolic Function in an Obese Skeletal Muscle Cell Culture Model.
  10. Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting STING-NLRP3 signaling pathway.
  11. Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function.
  12. Recent advances in skeletal muscle physiology.
  13. MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.
  14. Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases.
  15. Effects of carotenoids on mitochondrial dysfunction.
  16. Mitochondrial Dysfunction and Protein Homeostasis in Aging: Insights from a Premature-Aging Mouse Model.
  17. Resveratrol prevents age-related heart impairment through inhibiting the Notch/NF-κB pathway.
  18. Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.
  1. J Mass Spectrom Adv Clin Lab. 2024 Jan;31 49-58
    Development and validation of a multiplexed LC-MS/MS ketone body assay for clinical diagnostics.
    Robin H J Kemperman, Rebecca D Ganetzky, Stephen R Master.
      Objectives: Ketone bodies (KBs) serve as important energy sources that spare glucose, providing the primary energy for cardiac muscle, skeletal muscle during aerobic exercise, and the brain during periods of catabolism. The levels and relationships between the KBs are critical indicators of metabolic health and disease. However, challenges in separating isomeric KBs and concerns about sample stability have previously limited their clinical measurement.Methods: A novel 6.5-minute liquid chromatography-mass spectrometry-based assay was developed, enabling the precise measurement of alpha-, beta- and gamma-hydroxybutyrate, beta-hydroxyisobutyrate, and acetoacetate. This method was fully validated for human serum and plasma samples by investigating extraction efficiency, matrix effects, accuracy, recovery, intra- and inter-precision, linearity, lower limit of quantitation (LLOQ), carryover, specificity, stability, and more. From 107 normal samples, reference ranges were established for all analytes and the beta-hydroxybutyrate/acetoacetate ratio.
    Results: All five analytes were adequately separated chromatographically. An extraction efficiency between 80 and 120 % was observed for all KBs. Accuracy was evaluated through spike and recovery using 10 random patient samples, with an average recovery of 85-115 % for all KBs and a coefficient of variation of ≤ 3 %. Coefficients of variation for intra- and inter-day imprecision were < 5 %, and the total imprecision was < 10 %. No significant interferences were observed. Specimens remained stable for up to 6 h on ice or 2 h at room temperature.
    Conclusions: The developed method is highly sensitive and robust. It has been validated for use with human serum and plasma, overcoming stability concerns and providing a reliable and efficient quantitative estimation of ketone bodies.
    Keywords:  Acetoacetate; Beta-hydroxybutyrate; Clinical diagnostics; Ketone bodies; LC-MS/MS; Mitochondrial disease testing
    DOI:  https://doi.org/10.1016/j.jmsacl.2024.01.004
  2. Cells. 2024 Feb 06. pii: 294. [Epub ahead of print]13(4):
    Levels of Circulating Ketone Bodies in Patients Undergoing Cardiac Surgery on Cardiopulmonary Bypass.
    Anja Levis, Markus Huber, Déborah Mathis, Mark G Filipovic, Andrea Stieger, Lorenz Räber, Frank Stueber, Markus M Luedi.
      Ketone bodies (KBs) are energy-efficient substrates utilized by the heart depending on its metabolic demand and substrate availability. Levels of circulating KBs have been shown to be elevated in acute and chronic cardiovascular disease and are associated with severity of disease in patients with heart failure and functional outcome after myocardial infarction. To investigate whether this pattern similarly applies to patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB), we analysed prospectively collected pre- and postoperative blood samples from 192 cardiac surgery patients and compared levels and perioperative changes in total KBs with Troponin T as a marker of myocardial cell injury. We explored the association of patient characteristics and comorbidities for each of the two biomarkers separately and comparatively. Median levels of KBs decreased significantly over the perioperative period and inversely correlated with changes observed for Troponin T. Associations of patient characteristics with ketone body perioperative course showed notable differences compared to Troponin T, possibly highlighting factors acting as a "driver" for the change in the respective biomarker. We found an inverse correlation between perioperative change in ketone body levels and changes in troponin, indicating a marked decrease in ketone body concentrations in patients exhibiting greater myocardial cell injury. Further investigations aimed at better understanding the role of KBs on perioperative changes are warranted.
    Keywords:  3-hydroxybutyrate; acetoacetate; cardiopulmonary bypass; ischemia/reperfusion; ketone bodies
    DOI:  https://doi.org/10.3390/cells13040294
  3. Am J Physiol Endocrinol Metab. 2024 Feb 21.
    Relationship Between Serum β-Hydroxybutyrate and Hepatic Fatty Acid Oxidation in Individuals with Obesity and NAFLD.
    Mary P Moore, Grace Shryack, Isabella Alessi, Nicole Wieschhaus, Grace M Meers, Sarah A Johnson, Andrew A Wheeler, Jamal A Ibdah, Elizabeth J Parks, R Scott Rector.
      NAFLD is characterized by excess lipid accumulation which can progress to inflammation (NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly employed as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum (β-HB) levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142). Patients were stratified based on NAFLD activity Score (NAS): NAS=0 (no disease), NAS=1-2 (mild), NAS=3-4 (moderate), and NAS³5 (advanced). Moderate and advanced NAFLD associated with reductions in liver HMGCS2, serum β-HB, but not HMGCL mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum β-HB correlated with liver mitochondrial β-HAD activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum β-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD.
    Keywords:  HMGCS2; MASH; MASLD; ketones; mitochondria
    DOI:  https://doi.org/10.1152/ajpendo.00336.2023
  4. Metabolism. 2024 Feb 17. pii: S0026-0495(24)00044-1. [Epub ahead of print]154 155818
    Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation.
    Simran Pherwani, David Connolly, Qiuyu Sun, Qutuba G Karwi, Michael Carr, Kim L Ho, Cory S Wagg, Liyan Zhang, Jody Levasseur, Heidi Silver, Jason R B Dyck, Gary D Lopaschuk.
      BACKGROUND: Cardiac glucose oxidation is decreased in heart failure with reduced ejection fraction (HFrEF), contributing to a decrease in myocardial ATP production. In contrast, circulating ketones and cardiac ketone oxidation are increased in HFrEF. Since ketones compete with glucose as a fuel source, we aimed to determine whether increasing ketone concentration both chronically with the SGLT2 inhibitor, dapagliflozin, or acutely in the perfusate has detrimental effects on cardiac glucose oxidation in HFrEF, and what effect this has on cardiac ATP production.METHODS: 8-week-old male C57BL6/N mice underwent sham or transverse aortic constriction (TAC) surgery to induce HFrEF over 3 weeks, after which TAC mice were randomized to treatment with either vehicle or the SGLT2 inhibitor, dapagliflozin (DAPA), for 4 weeks (raises blood ketones). Cardiac function was assessed by echocardiography. Cardiac energy metabolism was measured in isolated working hearts perfused with 5 mM glucose, 0.8 mM palmitate, and either 0.2 mM or 0.6 mM β-hydroxybutyrate (βOHB).
    RESULTS: TAC hearts had significantly decreased %EF compared to sham hearts, with no effect of DAPA. Glucose oxidation was significantly decreased in TAC hearts compared to sham hearts and did not decrease further in TAC hearts treated with high βOHB or in TAC DAPA hearts, despite βOHB oxidation rates increasing in both TAC vehicle and TAC DAPA hearts at high βOHB concentrations. Rather, increasing βOHB supply to the heart selectively decreased fatty acid oxidation rates. DAPA significantly increased ATP production at both βOHB concentrations by increasing the contribution of glucose oxidation to ATP production.
    CONCLUSION: Therefore, increasing ketone concentration increases energy supply and ATP production in HFrEF without further impairing glucose oxidation.
    Keywords:  HFrEF; Ketone oxidation; SGLT2 inhibition
    DOI:  https://doi.org/10.1016/j.metabol.2024.155818
  5. Int J Mol Sci. 2024 Feb 08. pii: 2052. [Epub ahead of print]25(4):
    Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
    Emanuele Marzetti, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Anna Picca.
      Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation.
    Keywords:  DAMPs; extracellular vesicles; inflammaging; metabolism; mitochondrial DNA; mitochondrial biogenesis; mitochondrial transplantation; mitophagy; muscle aging; muscle plasticity
    DOI:  https://doi.org/10.3390/ijms25042052
  6. Int J Mol Sci. 2024 Feb 18. pii: 2410. [Epub ahead of print]25(4):
    The Structure of the Cardiac Mitochondria Respirasome Is Adapted for the β-Oxidation of Fatty Acids.
    Alexander V Panov.
      It is well known that in the heart and kidney mitochondria, more than 95% of ATP production is supported by the β-oxidation of long-chain fatty acids. However, the β-oxidation of fatty acids by mitochondria has been studied much less than the substrates formed during the catabolism of carbohydrates and amino acids. In the last few decades, several discoveries have been made that are directly related to fatty acid oxidation. In this review, we made an attempt to re-evaluate the β-oxidation of long-chain fatty acids from the perspectives of new discoveries. The single set of electron transporters of the cardiac mitochondrial respiratory chain is organized into three supercomplexes. Two of them contain complex I, a dimer of complex III, and two dimers of complex IV. The third, smaller supercomplex contains a dimer of complex III and two dimers of complex IV. We also considered other important discoveries. First, the enzymes of the β-oxidation of fatty acids are physically associated with the respirasome. Second, the β-oxidation of fatty acids creates the highest level of QH2 and reverses the flow of electrons from QH2 through complex II, reducing fumarate to succinate. Third, β-oxidation is greatly stimulated in the presence of succinate. We argue that the respirasome is uniquely adapted for the β-oxidation of fatty acids. The acyl-CoA dehydrogenase complex reduces the membrane's pool of ubiquinone to QH2, which is instantly oxidized by the smaller supercomplex, generating a high energization of mitochondria and reversing the electron flow through complex II, which reverses the electron flow through complex I, increasing the NADH/NAD+ ratio in the matrix. The mitochondrial nicotinamide nucleotide transhydrogenase catalyzes a hydride (H-, a proton plus two electrons) transfer across the inner mitochondrial membrane, reducing the cytosolic pool of NADP(H), thus providing the heart with ATP for muscle contraction and energy and reducing equivalents for the housekeeping processes.
    Keywords:  heart mitochondria; oxidative phosphorylation; respirasome; respiratory chain; tricarboxylic acid cycle; ubiquinol; ubiquinone; β-oxidation of fatty acids
    DOI:  https://doi.org/10.3390/ijms25042410
  7. Physiol Rep. 2024 Feb;12(4): e15952
    Lactate administration induces skeletal muscle synthesis by influencing Akt/mTOR and MuRF1 in non-trained mice but not in trained mice.
    Sunghwan Kyun, Jisu Kim, Deunsol Hwang, Inkwon Jang, Hun-Young Park, Kiwon Lim.
      The perception regarding lactate has changed over the past decades, and some of its physiological roles have gradually been revealed. However, the effects of exogenous lactate on skeletal muscle synthesis remain unclear. This study aimed to confirm the effects of a 5-week lactate administration and post-exercise lactate administration on skeletal muscle synthesis. Thirty-two Institute of Cancer Research mice were randomly assigned to non-trained + placebo, non-trained + lactate, trained + placebo, and trained + lactate groups. Furthermore, 3 g/kg of lactate or an equivalent volume of saline was immediately administered after exercise training (maximum oxygen uptake: 70%). Lactate administration and/or exercise training was performed 5 days/week for 5 weeks. After the experimental period, it was observed that lactate administration tended to elevate skeletal muscle weight, increased protein kinase B (p < 0.05) and mammalian target of rapamycin (p < 0.05) mRNA levels, and decreased muscle ring-finger protein-1 expression (p < 0.05). Lactate administration after exercise training significantly enhanced plantaris muscle weight; however, it had no additional effects on most signaling factors. This study demonstrated that a 5-week lactate administration could stimulate skeletal muscle synthesis, and lactate administration after exercise training may provide additional effects, such as increasing skeletal muscle.
    Keywords:  MuRF1; exercise; lactate; mTOR pathway; oral administration; protein synthesis
    DOI:  https://doi.org/10.14814/phy2.15952
  8. Nutrients. 2024 Feb 09. pii: 496. [Epub ahead of print]16(4):
    Magnesium and the Hallmarks of Aging.
    Ligia J Dominguez, Nicola Veronese, Mario Barbagallo.
      Magnesium is an essential ion in the human body that regulates numerous physiological and pathological processes. Magnesium deficiency is very common in old age. Age-related chronic diseases and the aging process itself are frequently associated with low-grade chronic inflammation, called 'inflammaging'. Because chronic magnesium insufficiency has been linked to excessive generation of inflammatory markers and free radicals, inducing a chronic inflammatory state, we formerly hypothesized that magnesium inadequacy may be considered among the intermediaries helping us explain the link between inflammaging and aging-associated diseases. We show in this review evidence of the relationship of magnesium with all the hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, disabled autophagy, dysbiosis, and chronic inflammation), which may positively affect the human healthspan. It is feasible to hypothesize that maintaining an optimal balance of magnesium during one's life course may turn out to be a safe and economical strategy contributing to the promotion of healthy aging. Future well-designed studies are necessary to further explore this hypothesis.
    Keywords:  aging; frailty; hallmarks of aging; healthy aging; magnesium; multimorbidity
    DOI:  https://doi.org/10.3390/nu16040496
  9. Nutrients. 2024 Feb 09. pii: 500. [Epub ahead of print]16(4):
    Effect of Short-Chain Fatty Acids on Inflammatory and Metabolic Function in an Obese Skeletal Muscle Cell Culture Model.
    Kelsey Van, Jessie L Burns, Jennifer M Monk.
      The fermentation of non-digestible carbohydrates produces short-chain fatty acids (SCFAs), which have been shown to impact both skeletal muscle metabolic and inflammatory function; however, their effects within the obese skeletal muscle microenvironment are unknown. In this study, we developed a skeletal muscle in vitro model to mimic the critical features of the obese skeletal muscle microenvironment using L6 myotubes co-treated with 10 ng/mL lipopolysaccharide (LPS) and 500 µM palmitic acid (PA) for 24 h ± individual SCFAs, namely acetate, propionate and butyrate at 0.5 mM and 2.5 mM. At the lower SCFA concentration (0.5 mM), all three SCFA reduced the secreted protein level of RANTES, and only butyrate reduced IL-6 protein secretion and the intracellular protein levels of activated (i.e., ratio of phosphorylated-total) NFκB p65 and STAT3 (p < 0.05). Conversely, at the higher SCFA concentration (2.5 mM), individual SCFAs exerted different effects on inflammatory mediator secretion. Specifically, butyrate reduced IL-6, MCP-1 and RANTES secretion, propionate reduced IL-6 and RANTES, and acetate only reduced RANTES secretion (p < 0.05). All three SCFAs reduced intracellular protein levels of activated NFκB p65 and STAT3 (p < 0.05). Importantly, only the 2.5 mM SCFA concentration resulted in all three SCFAs increasing insulin-stimulated glucose uptake compared to control L6 myotube cultures (p < 0.05). Therefore, SCFAs exert differential effects on inflammatory mediator secretion in a cell culture model, recapitulating the obese skeletal muscle microenvironment; however, all three SCFAs exerted a beneficial metabolic effect only at a higher concentration via increasing insulin-stimulated glucose uptake, collectively exerting differing degrees of a beneficial effect on obesity-associated skeletal muscle dysfunction.
    Keywords:  L6 myotubes; chemokines; cytokines; inflammation; insulin-stimulated glucose uptake; lipopolysaccharide; myokines; obesity; palmitic acid; short-chain fatty acids; skeletal muscle
    DOI:  https://doi.org/10.3390/nu16040500
  10. Mol Cell Biochem. 2024 Feb 22.
    Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting STING-NLRP3 signaling pathway.
    Zujie Xu, Zheying Ma, Xiaoqin Zhao, Bing Zhang.
      Obesity has been identified as an independent risk factor for cardiovascular disease. Recent reports have highlighted the significance of stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) signaling pathway mediated pyroptosis, and inflammation in cardiovascular disease. Previous studies have demonstrated that exercise training effectively prevents cardiac pyroptosis and inflammation in high-fat diet (HFD)-fed mice. However, it is currently unknown whether exercise reduces pyroptosis and inflammation in obese hearts by targeting the STING-NLRP3 signaling pathway. We investigated the impact of an 8-week aerobic exercise regimen on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 signaling pathway in HFD-induced obese mice. Additionally, to explore the underlying mechanism of STING in exercise-mediated cardioprotection, we administered intraperitoneal injections of the STING agonist diABZI to the mice. Furthermore, to investigate the role of the STING-NLRP3 signaling pathway in HFD-induced cardiac dysfunction, we administered adeno-associated virus 9 (AAV9) encoding shRNA targeting STING (shRNA-STING) via tail vein injection to knockdown STING expression specifically in mouse hearts. After one week of AAV9 injection, we intraperitoneally injected nigericin as an NLRP3 agonist. We first found that aerobic exercise effectively suppressed HFD-mediated upregulation of STING and NLRP3 in the hearts. Moreover, we demonstrated that the protective effect of aerobic exercise in HFD-induced cardiac dysfunction, pyroptosis, and inflammation was impaired by stimulating the STING pathway using diABZI. Additionally, activation of the NLRP3 with nigericin abolished the ameliorative effect of STING deficiency in HFD-induced cardiac dysfunction, pyroptosis, and inflammation. Based on these findings, we concluded that 8-week aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting STING-NLRP3 signaling pathway. Inhibition of STING-NLRP3 signaling pathway may serve as a promising therapeutic strategy against obesity-induced cardiomyopathy.
    Keywords:  Aerobic exercise; High-fat diet (HFD); Inflammation; Obesity-induced cardiomyopathy; Pyroptosis; STING-NLRP3
    DOI:  https://doi.org/10.1007/s11010-024-04950-0
  11. Sci Rep. 2024 02 21. 14(1): 4331
    Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function.
    Kaitlin Kiernan, Yazan Alwarawrah, Amanda G Nichols, Keiko Danzaki, Nancie J MacIver.
      Insulin and insulin-like growth factor 1 (IGF-1) are metabolic hormones with known effects on CD4+ T cells through insulin receptor (IR) and IGF-1 receptor (IGF-1R) signaling. Here, we describe specific and distinct roles for these hormones and receptors. We have found that IGF-1R, but not IR, expression is increased following CD4+ T cell activation or following differentiation toward Th17 cells. Although both insulin and IGF-1 increase the metabolism of CD4+ T cells, insulin has a more potent effect. However, IGF-1 has a unique role and acts specifically on Th17 cells to increase IL-17 production and Th17 cell metabolism. Furthermore, IGF-1 decreases mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS) in Th17 cells, providing a cytoprotective effect. Interestingly, both IR and IGF-1R are required for this effect of IGF-1 on mitochondria, which suggests that the hybrid IR/IGF-1R may be required for mediating the effect of IGF-1 on mitochondrial membrane potential and mROS production.
    DOI:  https://doi.org/10.1038/s41598-024-54836-w
  12. BJA Educ. 2024 Mar;24(3): 84-90
    Recent advances in skeletal muscle physiology.
    V Kaura, P M Hopkins.
      
    Keywords:  excitation–contraction coupling; malignant hyperthermia; muscle fatigue; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.bjae.2023.12.003
  13. Acta Physiol (Oxf). 2024 Feb 23. e14119
    MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.
    Marina Cefis, Manon Dargegen, Vincent Marcangeli, Shima Taherkhani, Maude Dulac, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Sabah N A Hussain, Gilles Gouspillou.
      AIM: Sarcopenia, the aging-related loss of muscle mass and function, is a debilitating process negatively impacting the quality of life of affected individuals. Although the mechanisms underlying sarcopenia are incompletely understood, impairments in mitochondrial dynamics, including mitochondrial fusion, have been proposed as a contributing factor. However, the potential of upregulating mitochondrial fusion proteins to alleviate the effects of aging on skeletal muscles remains unexplored. We therefore hypothesized that overexpressing Mitofusin 2 (MFN2) in skeletal muscle in vivo would mitigate the effects of aging on muscle mass and improve mitochondrial function.METHODS: MFN2 was overexpressed in young (7 mo) and old (24 mo) male mice for 4 months through intramuscular injections of an adeno-associated viruses. The impacts of MFN2 overexpression on muscle mass and fiber size (histology), mitochondrial respiration, and H2 O2 emission (Oroboros fluororespirometry), and various signaling pathways (qPCR and western blotting) were investigated.
    RESULTS: MFN2 overexpression increased muscle mass and fiber size in both young and old mice. No sign of fibrosis, necrosis, or inflammation was found upon MFN2 overexpression, indicating that the hypertrophy triggered by MFN2 overexpression was not pathological. MFN2 overexpression even reduced the proportion of fibers with central nuclei in old muscles. Importantly, MFN2 overexpression had no impact on muscle mitochondrial respiration and H2 O2 emission in both young and old mice. MFN2 overexpression attenuated the increase in markers of impaired autophagy in old muscles.
    CONCLUSION: MFN2 overexpression may be a viable approach to mitigate aging-related muscle atrophy and may have applications for other muscle disorders.
    Keywords:  autophagy; mitochondria; mitochondrial dynamics; mitochondrial fusion; mitofusin 2; sarcopenia; skeletal muscle aging
    DOI:  https://doi.org/10.1111/apha.14119
  14. EMBO Mol Med. 2024 Feb 21.
    Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases.
    Doris Krauter, Daniela Stausberg, Timon J Hartmann, Stefan Volkmann, Theresa Kungl, David A Rasche, Gesine Saher, Robert Fledrich, Ruth M Stassart, Klaus-Armin Nave, Sandra Goebbels, David Ewers, Michael W Sereda.
      Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), characterized by hypomyelination of medium to large caliber axons. The molecular mechanisms of abnormal myelin growth regulation by PMP22 have remained obscure. Here, we show in rodent models of HNPP and CMT1A that the PI3K/Akt/mTOR-pathway inhibiting phosphatase PTEN is correlated in abundance with PMP22 in peripheral nerves, without evidence for direct protein interactions. Indeed, treating DRG neuron/Schwann cell co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination. When we treated HNPP mice in vivo with the mTOR inhibitor Rapamycin, motor functions were improved, compound muscle amplitudes were increased and pathological tomacula in sciatic nerves were reduced. In contrast, we found Schwann cell dedifferentiation in CMT1A uncoupled from PI3K/Akt/mTOR, leaving partial PTEN ablation insufficient for disease amelioration. For HNPP, the development of PI3K/Akt/mTOR pathway inhibitors may be considered as the first treatment option for pressure palsies.
    Keywords:  Charcot–Marie–Tooth Neuropathies; Myelin; PI3K/Akt/mTOR Signaling; Peripheral Myelin Protein of 22 kDa; Schwann Cell
    DOI:  https://doi.org/10.1038/s44321-023-00019-5
  15. Biochem Soc Trans. 2024 Feb 22. pii: BST20230193. [Epub ahead of print]
    Effects of carotenoids on mitochondrial dysfunction.
    Opeyemi Stella Ademowo, Olubukola Oyebode, Roshita Edward, Myra E Conway, Helen R Griffiths, Irundika H K Dias.
      Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrial-derived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for age-related diseases.
    Keywords:  astaxanthin; carotenoids; mitochondria; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1042/BST20230193
  16. Biomolecules. 2024 Jan 30. pii: 162. [Epub ahead of print]14(2):
    Mitochondrial Dysfunction and Protein Homeostasis in Aging: Insights from a Premature-Aging Mouse Model.
    Jaime M Ross, Lars Olson, Giuseppe Coppotelli.
      Mitochondrial dysfunction has been implicated in aging and age-related disorders. Disturbed-protein homeostasis and clearance of damaged proteins have also been linked to aging, as well as to neurodegenerative diseases, cancers, and metabolic disorders. However, since mitochondrial oxidative phosphorylation, ubiquitin-proteasome, and autophagy-lysosome systems are tightly interdependent, it is not understood whether the facets observed in aging are the causes or consequences of one or all of these failed processes. We therefore used prematurely aging mtDNA-mutator mice and normally aging wild-type littermates to elucidate whether mitochondrial dysfunction per se is sufficient to impair cellular protein homeostasis similarly to that which is observed in aging. We found that both mitochondrial dysfunction and normal aging affect the ubiquitin-proteasome system in a tissue-dependent manner, whereas only normal aging markedly impairs the autophagy-lysosome system. Thus, our data show that the proteostasis network control in the prematurely aging mtDNA-mutator mouse differs in certain aspects from that found in normal aging. Taken together, our findings suggest that severe mitochondrial dysfunction drives an aging phenotype associated with the impairment of certain components of the protein homeostasis machinery, while others, such as the autophagy-lysosome system, are not affected or only minimally affected. Taken together, this shows that aging is a multifactorial process resulting from alterations of several integrated biological processes; thus, manipulating one process at the time might not be sufficient to fully recapitulate all changes associated with normal aging.
    Keywords:  aging; autophagy; mitochondrial dysfunction; ubiquitin–proteasome system
    DOI:  https://doi.org/10.3390/biom14020162
  17. Food Sci Nutr. 2024 Feb;12(2): 1035-1045
    Resveratrol prevents age-related heart impairment through inhibiting the Notch/NF-κB pathway.
    Le-Feng Wang, Wen-Juan Li, Xian-Yi Zhang, Yi-Chi Zhang, Guang-Feng Chen, Xing-Yu Zhou, Dong-Mei Xv, Qiong Wu.
      Resveratrol (RSV) is a natural polyphenol compound found in various plants that has been shown to have potential benefits for preventing aging and supporting cardiovascular health. However, the specific signal pathway by which RSV protects the aging heart is not yet well understood. This study aimed to explore the protective effects of RSV against age-related heart injury and investigate the underlying mechanisms using a D-galactose-induced aging model. The results of the study indicated that RSV provided protection against age-related heart impairment in mice. This was evidenced by the reduction of cardiac histopathological changes as well as the attenuation of apoptosis. RSV-induced cardioprotection was linked to a significant increase in antioxidant activity and mitochondrial transmembrane potential, as well as a reduction in oxidative damage. Additionally, RSV inhibited the production of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, the expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), and notch 1 protein were inhibited by RSV, indicating that inhibiting the Notch/NF-κB pathway played a critical role in RSV-triggered heart protection in aging mice. Moreover, further data on intestinal function demonstrated that RSV significantly increased short-chain fatty acids (SCFAs) in intestinal contents and reduced the pH value in the feces of aging mice. RSV alleviated aging-induced cardiac dysfunction through the suppression of oxidative stress and inflammation via the Notch/NF-κB pathway in heart tissue. Furthermore, this therapeutic effect was found to be associated with its protective roles in the intestine.
    Keywords:  Notch/NF‐κB pathways; aging; heart impairment; inflammation; oxidative stress; resveratrol
    DOI:  https://doi.org/10.1002/fsn3.3817
  18. Biology (Basel). 2024 Feb 11. pii: 116. [Epub ahead of print]13(2):
    Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.
    Rosalba Senese, Giuseppe Petito, Elena Silvestri, Maria Ventriglia, Nicola Mosca, Nicoletta Potenza, Aniello Russo, Francesco Manfrevola, Gilda Cobellis, Teresa Chioccarelli, Veronica Porreca, Vincenza Grazia Mele, Rosanna Chianese, Pieter de Lange, Giulia Ricci, Federica Cioffi, Antonia Lanni.
      This study aims to explore the complex role of cannabinoid type 1 receptor (CB1) signaling in the gastrocnemius muscle, assessing physiological processes in both CB1+/+ and CB1-/- mice. The primary focus is to enhance our understanding of how CB1 contributes to mitochondrial homeostasis. At the tissue level, CB1-/- mice exhibit a substantial miRNA-related alteration in muscle fiber composition, characterized by an enrichment of oxidative fibers. CB1 absence induces a significant increase in the oxidative capacity of muscle, supported by elevated in-gel activity of Complex I and Complex IV of the mitochondrial respiratory chain. The increased oxidative capacity is associated with elevated oxidative stress and impaired antioxidant defense systems. Analysis of mitochondrial biogenesis markers indicates an enhanced capacity for new mitochondria production in CB1-/- mice, possibly adapting to altered muscle fiber composition. Changes in mitochondrial dynamics, mitophagy response, and unfolded protein response (UPR) pathways reveal a dynamic interplay in response to CB1 absence. The interconnected mitochondrial network, influenced by increased fusion and mitochondrial UPR components, underlines the dual role of CB1 in regulating both protein quality control and the generation of new mitochondria. These findings deepen our comprehension of the CB1 impact on muscle physiology, oxidative stress, and MQC processes, highlighting cellular adaptability to CB1-/-. This study paves the way for further exploration of intricate signaling cascades and cross-talk between cellular compartments in the context of CB1 and mitochondrial homeostasis.
    Keywords:  cannabinoid type 1 receptor (CB1); miRNA; mitochondria; mitochondrial quality control (MQC); mitochondrial unfolded protein response (UPRmt); skeletal muscle
    DOI:  https://doi.org/10.3390/biology13020116
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