bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023‒04‒09
seventeen papers selected by
Matías Javier Monsalves Álvarez
  1. Ketogenic Diet Alleviates Renal Interstitial Fibrosis in UUO Mice by Regulating Macrophage Proliferation.
  2. Effects of very low-calorie ketogenic diet on hypothalamic-pituitary-adrenal axis and renin-angiotensin-aldosterone system.
  3. Regulatory effects of ketogenic diet on the inflammatory response in obese Saudi women.
  4. Efficacy of very low-calorie ketogenic diet with the Pronokal® method in obese women with polycystic ovary syndrome: a 16-week randomized controlled trial.
  5. Effects of a ketogenic and low-fat diet on the human metabolome, microbiome, and foodome in adults at risk for Alzheimer's disease.
  6. Skeletal muscle single fiber force production declines early in juvenile male mice with chronic kidney disease.
  7. Human skeletal muscle methylome after low carbohydrate energy balanced exercise.
  8. Mitochondria in Health, Disease, and Ageing.
  9. Low carbohydrate intake correlates with trends of insulin resistance and metabolic acidosis in healthy lean individuals.
  10. The impact of a story on learning ketone body metabolism.
  11. Mediterranean diet and mitochondria: New findings.
  12. Skeletal muscle health: A key determinant of healthy aging.
  13. The transcription regulator ATF4 is a mediator of skeletal muscle aging.
  14. Mitochondrial fumarate implicated in inflammation.
  15. Exercise Training in Heart Failure With Preserved Ejection Fraction: Is the Peripheral Vasculature Involved?
  16. Inhibition of LPS‑induced NLRP3 inflammasome activation by stem cell‑conditioned culture media in human gingival epithelial cells.
  17. TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.
  1. J Nutr Biochem. 2023 Apr 04. pii: S0955-2863(23)00068-2. [Epub ahead of print] 109335
    Ketogenic Diet Alleviates Renal Interstitial Fibrosis in UUO Mice by Regulating Macrophage Proliferation.
    Xiaofan Hu, Yang Qiu, Rui Cao, Cong Xu, Chenqi Lu, Zhimin Wang, Jun Yang.
      The ketogenic diet (KD), a high-fat and extremely low-carbohydrate dietary regimen, has long been acknowledged as a highly beneficial dietary therapy for the treatment of intractable epilepsy throughout the last decade. Because of its significant therapeutic potential for a variety of ailments, KD is increasingly attracting study interest. In renal fibrosis, KD has received little attention. This study aimed to determine whether KD protects against renal fibrosis in unilateral ureteral obstruction (UUO) models and the possible mechanisms. The ketogenic diet, according to our findings, reduces UUO-induced kidney injury and fibrosis in mice. KD dramatically decreased the number of F4/80+macrophages in kidneys. Next, immunofluorescence results revealed a reduction in the number of F4/80+Ki67+macrophages in the KD group. Furthermore, our study evaluated the impact of β-hydroxybutyric acid (β-OHB) in RAW246.7 macrophages in vitro. We found that β-OHB inhibits macrophage proliferation. Mechanistically, β-OHB inhibits macrophage proliferation may be via the FFAR3-AKT pathway. Collectively, our study indicated that KD ameliorates UUO-induced renal fibrosis by regulating macrophage proliferation. KD may be an effective therapy method for renal fibrosis due to its protective impact against the disorder.
    Keywords:  ketogenic diet; macrophage; renal fibrosis; unilateral ureteral obstruction; β -hydroxybutyric acid
    DOI:  https://doi.org/10.1016/j.jnutbio.2023.109335
  2. J Endocrinol Invest. 2023 Apr 05.
    Effects of very low-calorie ketogenic diet on hypothalamic-pituitary-adrenal axis and renin-angiotensin-aldosterone system.
    L Barrea, L Verde, E Camajani, A S Šojat, L Marina, S Savastano, A Colao, M Caprio, G Muscogiuri.
      BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system involved in controlling stress responses in humans under physiological and pathological conditions; cortisol is the main hormone produced by the HPA axis. It is known that calorie restriction acts as a stressor and can lead to an increase in cortisol production. Renin-angiotensin-aldosterone system (RAAS) is a complex endocrine network regulating blood pressure and hydrosaline metabolism, whose final hormonal effector is aldosterone. RAAS activation is linked to cardiometabolic diseases, such as heart failure and obesity. Obesity has become a leading worldwide pandemic, associated with serious health outcomes. Calorie restriction represents a pivotal strategy to tackle obesity. On the other hand, it is well known that an increased activity of the HPA may favour visceral adipose tissue expansion, which may jeopardize a successful diet-induced weight loss. Very low-calorie ketogenic diet (VLCKD) is a normoprotein diet with a drastic reduction of the carbohydrate content and total calorie intake. Thanks to its sustained protein content, VLCKD is extremely effective to reduce adipose tissue while preserving lean body mass and resting metabolic rate.PURPOSE: The purpose of this narrative review is to gain more insights on the effects of VLCKD on the HPA axis and RAAS, in different phases of weight loss and in different clinical settings.
    Keywords:  Cortisol; Diet; HPA axis; Obesity; Stress; Very low-calorie ketogenic diet
    DOI:  https://doi.org/10.1007/s40618-023-02068-6
  3. J Taibah Univ Med Sci. 2023 Oct;18(5): 1101-1107
    Regulatory effects of ketogenic diet on the inflammatory response in obese Saudi women.
    Nada Alkhorayef, Fatimah T Almutery, Zafar Rasheed, Sami A Althwab, Abdullah S M Aljohani, Yasser A N Alhawday, Tarek Salem, Abdulaziz M Alharbi, Abdulrahman A A B Wahaq, Fawaz S Alharbi, Abdulrhman S Alghanem, Waleed Al Abdulmonem.
      Objective: In recent years, the use of a ketogenic diet (KD) against obesity has gained popularity in KSA. This study was designed to determine the impact of KD on anthropometric indices and on the abnormal regulation of inflammatory activities in obese Saudi women. Moreover, we investigated the potential of beta-hydroxybutyrate (BHB) supplementation on the inhibition of pro-inflammatory activities.Methods: We enrolled 31 Saudi women (aged, 35.3 ± 8.4 years) with an average BMI of 33.96 ± 4.44 kg/m2 underwent an 8-week KD (8KD) from January to March 2021. Changes in anthropometric measurements were collected at baseline and after 4-8 weeks of intervention. Compliance with the dietary regimen was monitored weekly by plasma BHB level.
    Results: Twenty-nine females commenced the diets and 23 completed the study (a 79% completion rate). In comparison to pre-intervention, the 8KD resulted in a significant increase in the levels of plasma BHB (P < 0.001) throughout the duration of the trial. This was accompanied by a significant reduction in weight loss (7.7 kg ± 11.3; P < 0.001), BMI, waist circumference (P < 0.001), and levels of the inflammatory cytokine IL-1β (P < 0.001).
    Conclusions: An 8-week KD was found to be useful in producing a positive impact on anthropometric indices, biochemical and inflammatory processes. This study indicated that the intake of a KD by obese Saudi women induced the release of BHB in the blood without stimulation of an overall starvation response. This may be useful to alleviate the severity of chronic inflammatory disorders associated with obesity.
    Keywords:  Inflammation; Ketogenic diet; Obesity; Saudi; Women
    DOI:  https://doi.org/10.1016/j.jtumed.2023.03.006
  4. Endocr Connect. 2023 Apr 01. pii: EC-22-0536. [Epub ahead of print]
    Efficacy of very low-calorie ketogenic diet with the Pronokal® method in obese women with polycystic ovary syndrome: a 16-week randomized controlled trial.
    Srdjan Pandurevic, Ilaria Mancini, Dimitri Mitselman, Matteo Magagnoli, Rita Teglia, Roberta Fazzeri, Paola Dionese, Carolina Cecchetti, Massimiliano Caprio, Constanzo Moretti, Justyna Sicinska, Alessandro Agostini, Domenica Gazineo, Lea Godino, Ignacio Sajoux, Flaminia Fanelli, Cristina M Meriggiola, Uberto Pagotto, Alessandra Gambineri.
      OBJECTIVE: To assess the efficacy of a very low-calorie ketogenic diet (VLCKD) method versus a Mediterranean low-calorie diet (LCD) in obese PCOS women of a reproductive age.DESIGN: Randomized controlled open label trial. The treatment period was 16 weeks; VLCKD for 8 weeks then LCD for 8 weeks, according to the Pronokal® method (experimental group; n=15) versus Mediterranean LCD for 16 weeks (control group; n=15). Ovulation monitoring was carried out at baseline and after 16 weeks, while a clinical exam, bioelectrical impedance analysis (BIA), anthropometry, and biochemical analyses were performed at baseline, at week 8, and at week 16.
    RESULTS: BMI decreased significantly in both groups, and to a major extent in the experimental group (-13.7% vs -5.1%, p=0.0003). Significant differences between the experimental and the control groups were also observed in the reduction of waist circumference (-11.4% vs -2.9%), BIA-measured body fat (-24.0% vs -8.1%), and free T (-30.4% vs -12.6%) after 16 weeks (p=0.0008, p=0.0176, and p=0.0009, respectively). HOMA-IR significantly decreased only in the experimental group (p=0.0238), but without significant differences with respect to the control group (-23% vs -13.2%, p>0.05). At baseline, 38.5% participants in the experimental group and 14.3% participants in the control group had ovulation, which increased to 84.6% (p=0.031) and 35.7% (p>0.05) at the end of the study, respectively.
    CONCLUSION: In obese PCOS patients, 16-weeks of VLCKD protocol with the Pronokal® method was more effective than Mediterranean LCD in reducing total and visceral fat, and in ameliorating hyperandrogenism and ovulatory dysfunction.
    DOI:  https://doi.org/10.1530/EC-22-0536
  5. Alzheimers Dement. 2023 Apr 05.
    Effects of a ketogenic and low-fat diet on the human metabolome, microbiome, and foodome in adults at risk for Alzheimer's disease.
    Alzheimer's Gut Microbiome Project Consortium
      INTRODUCTION: The ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential for KD-mediated neuroprotection against seizures as well as modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis of gut microbiota and metabolites related to cognitive status following a controlled KD intervention compared with a low-fat-diet intervention.METHODS: Prediabetic adults, either with mild cognitive impairment (MCI) or cognitively normal (CN), were placed on either a low-fat American Heart Association diet or high-fat modified Mediterranean KD (MMKD) for 6 weeks; then, after a 6-week washout period, they crossed over to the alternate diet. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five time points to investigate individuals' microbiome and metabolome throughout the dietary interventions.
    RESULTS: Participants with MCI on the MMKD had lower levels of GABA-producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA-regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had lower levels of bile salt hydrolase-containing microbes and an altered bile acid pool, suggesting reduced gut motility.
    DISCUSSION: Our results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut-transit time.
    Keywords:  Alzheimer's disease; ketogenic diet; low-fat American Heart Association Diet (AHAD); metabolome; microbiome; mild cognitive impairment
    DOI:  https://doi.org/10.1002/alz.13007
  6. Physiol Rep. 2023 Apr;11(7): e15651
    Skeletal muscle single fiber force production declines early in juvenile male mice with chronic kidney disease.
    Brent A Momb, Edwin Patino, Oleh M Akchurin, Mark S Miller.
      Children with chronic kidney disease (CKD) frequently exhibit delayed physical development and reduced physical performance, presumably due to skeletal muscle dysfunction. However, the cellular and molecular basis of skeletal muscle impairment in juvenile CKD remains poorly understood. Cellular (single fiber) and molecular (myosin-actin interactions and myofilament properties) function was examined ex vivo in slow (soleus) and fast (extensor digitorum longus) contracting muscles of juvenile male (6 weeks old) CKD and control mice. CKD was induced by 0.2% adenine diet for 3 weeks starting at 3 weeks of age. Specific tension (maximal isometric force divided by cross-sectional area) was reduced in larger myosin heavy chain (MHC) I and IIA fibers and in all IIB fibers in juvenile male mice with CKD due to fewer strongly bound myosin-actin cross-bridges. Fiber cross-sectional area in juvenile CKD mice was unchanged in MHC I and IIB fibers and increased in MHC IIA fibers, compared to controls. CKD slowed cross-bridge kinetics (slower rate of myosin force production and longer myosin attachment time, ton ) in MHC IIA fibers, and accelerated kinetics (shorter ton ) in MHC IIB fibers, which may indicate fiber type dependent shifts in contractile velocity in juvenile CKD. Overall, our findings show that single fiber myopathy is an early event during juvenile CKD, manifesting prior to the development of cellular atrophy as reduced force generation due to fewer strongly bound myosin heads. These results warrant clinical translation and call for early interventions to preserve physical function in children with CKD.
    Keywords:  chronic kidney disease; cross-bridge; myosin; pediatric; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.15651
  7. Am J Physiol Endocrinol Metab. 2023 Apr 05.
    Human skeletal muscle methylome after low carbohydrate energy balanced exercise.
    Piotr P Gorski, Daniel C Turner, Juma Iraki, James P Morton, Adam P Sharples, José L Areta.
      We aimed to investigate the human skeletal muscle (SkM) DNA methylome after exercise in low carbohydrate (CHO) energy balance (with high fat) compared with exercise in low-CHO energy deficit (with low fat) conditions. The objective to identify novel epigenetically regulated genes and pathways associated with 'train-low sleep-low' paradigms. The sleep-low conditions included 9 males that cycled to deplete muscle glycogen while reaching a set energy expenditure. Post-exercise, low-CHO meals (protein-matched) completely replaced (using high-fat) or only partially replaced (low-fat) the energy expended. The following morning resting baseline biopsies were taken and the participants then undertook 75 minutes of cycling exercise, with skeletal muscle biopsies collected 30 minutes and 3.5 hours post exercise. Discovery of genome-wide DNA methylation was undertaken using Illumina EPIC arrays and targeted gene expression analysis was conducted by RT-qPCR. At baseline participants under energy balance (high fat) demonstrated a predominantly hypermethylated (60%) profile across the genome compared to energy deficit-low fat conditions. However, post exercise performed in energy balance (with high fat) elicited a more prominent hypomethylation signature 30 minutes post-exercise in gene regulatory regions important for transcription (CpG islands within promoter regions) compared with exercise in energy deficit (with low fat) conditions. Such hypomethylation was enriched within pathways related to: IL6-JAK-STAT signalling, metabolic processes, p53 / cell cycle and oxidative / fatty acid metabolism. Hypomethylation within the promoter regions of genes: HDAC2, MECR, IGF2 and c13orf16 were associated with significant increases in gene expression in the post-exercise period in energy balance compared with energy deficit. Furthermore, histone deacetylase, HDAC11 was oppositely regulated at the gene expression level compared with HDAC2, where HDAC11 was hypomethylated yet increased in energy deficit compared with energy balance conditions. Overall, we identify some novel epigenetically regulated genes associated with train-low sleep-low paradigms.
    Keywords:  HDAC; exercise; low CHO; methylome
    DOI:  https://doi.org/10.1152/ajpendo.00029.2023
  8. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  9. Front Public Health. 2023 ;11 1115333
    Low carbohydrate intake correlates with trends of insulin resistance and metabolic acidosis in healthy lean individuals.
    Fatema Al-Reshed, Sardar Sindhu, Ashraf Al Madhoun, Fatemah Bahman, Halemah AlSaeed, Nadeem Akhter, Md Zubbair Malik, Fawaz Alzaid, Fahd Al-Mulla, Rasheed Ahmad.
      Introduction: Both obesity and a poor diet are considered major risk factors for triggering insulin resistance syndrome (IRS) and the development of type 2 diabetes mellitus (T2DM). Owing to the impact of low-carbohydrate diets, such as the keto diet and the Atkins diet, on weight loss in individuals with obesity, these diets have become an effective strategy for a healthy lifestyle. However, the impact of the ketogenic diet on IRS in healthy individuals of a normal weight has been less well researched. This study presents a cross-sectional observational study that aimed to investigate the effect of low carbohydrate intake in healthy individuals of a normal weight with regard to glucose homeostasis, inflammatory, and metabolic parameters.Methods: The study included 120 participants who were healthy, had a normal weight (BMI 25 kg/m2), and had no history of a major medical condition. Self-reported dietary intake and objective physical activity measured by accelerometry were tracked for 7 days. The participants were divided into three groups according to their dietary intake of carbohydrates: the low-carbohydrate (LC) group (those consuming <45% of their daily energy intake from carbohydrates), the recommended range of carbohydrate (RC) group (those consuming 45-65% of their daily energy intake from carbohydrates), and the high-carbohydrate (HC) group (those consuming more than 65% of their daily energy intake from carbohydrates). Blood samples were collected for the analysis of metabolic markers. HOMA of insulin resistance (HOMA-IR) and HOMA of β-cell function (HOMA-β), as well as C-peptide levels, were used for the evaluation of glucose homeostasis.
    Results: Low carbohydrate intake (<45% of total energy) was found to significantly correlate with dysregulated glucose homeostasis as measured by elevations in HOMA-IR, HOMA-β% assessment, and C-peptide levels. Low carbohydrate intake was also found to be coupled with lower serum bicarbonate and serum albumin levels, with an increased anion gap indicating metabolic acidosis. The elevation in C-peptide under low carbohydrate intake was found to be positively correlated with the secretion of IRS-related inflammatory markers, including FGF2, IP-10, IL-6, IL-17A, and MDC, but negatively correlated with IL-3.
    Discussion: Overall, the findings of the study showed that, for the first time, low-carbohydrate intake in healthy individuals of a normal weight might lead to dysfunctional glucose homeostasis, increased metabolic acidosis, and the possibility of triggering inflammation by C-peptide elevation in plasma.
    Keywords:  C-peptide; HOMA-IR; anion gap; inflammation; insulin resistance; low carbohydrate
    DOI:  https://doi.org/10.3389/fpubh.2023.1115333
  10. Biochem Mol Biol Educ. 2023 Apr 05.
    The impact of a story on learning ketone body metabolism.
    Génesis Romero-Zambrano, Fernando Valdivieso-Rivera, José Rafael Almeida.
      Biochemistry is a core subject in the cross-disciplinary training on Biotechnology engineering courses. Metabolic pathways teaching has traditionally integrated hands-on laboratory experiences and traditional lectures, which detail a large number of reactions at a molecular level, their enzymes and regulation. The current scenario of Covid-19 outbreak have motivated the development of complementary tools that expand the horizon of metabolism teaching. In this study, we employed a story-based methodology to strengthen the metabolic pathways learning and to measure students' perception. Specifically, a peer-reviewed tale describing the ketone body metabolism was used during five semesters as a didactic strategy to teach this biochemical process. A questionnaire assessed the students' understanding and acceptance of the methodology (n = 83). Our findings showed that a high proportion of students (83.13%) were able to relate the story to the topics studied in the classroom (ketogenesis and ketolysis). On the other hand, they were satisfied and suggested that such methodology is effective and fun. In summary, most of the survey responses related to acceptance of story-based strategy ranged from 72% to 97%. Collectively, these results indicated that the story is appropriate to decomplex pathways, becoming a simple tool for driving motivation, learning and engagement of students. The narrative represents a bridge to connect the intriguing series of chemical reactions involved in the anabolism and degradation of 3-hydroxybutyrate (3-OHB), acetoacetate, and acetone with previously learned knowledge, emotions, and key concepts. In conclusion, the tale was useful to decode ketone body-related pathways and making metabolism learning more interesting and easier.
    Keywords:  ketogenesis; ketolysis; metabolic pathway; story
    DOI:  https://doi.org/10.1002/bmb.21732
  11. Exp Gerontol. 2023 Apr 05. pii: S0531-5565(23)00086-4. [Epub ahead of print]176 112165
    Mediterranean diet and mitochondria: New findings.
    Francesco Pollicino, Nicola Veronese, Ligia J Dominguez, Mario Barbagallo.
      Mitochondria are subcellular organelles known for their central role in several energetic processes. Accumulating evidence supports a key role for mitochondria in the physiological response to both acute and chronic stress exposure, and, ultimately, the biological embedding of adversity in health and psychological functioning that increases the interest of these organelles in several medical conditions typical of older people. At the same time, Mediterranean diet (MedDiet) seems to affect the function of mitochondria further justifying the role of this diet in lowering the risk of negative health outcomes. In this review, we have elucidated the role of mitochondria in human diseases including the fundamental role in stress, aging, and neuropsychiatric and metabolic disorders. Overall, MedDiet can limit the production of free radicals, being rich in polyphenols. Moreover, MedDiet reduced mitochondrial reactive oxygen species (mtROS) production and ameliorated mitochondrial damage and apoptosis. Similarly, whole grains can maintain the mitochondrial respiration and membrane potential, finally improving mitochondrial function. Other components of MedDiet can have anti-inflammatory effects, again modulating mitochondrial function. For example, delphinidin (a flavonoid present in red wine and berries) restored the elevated level of mitochondrial respiration, mtDNA content, and complex IV activity; similarly, resveratrol and lycopene, present in grapefruits and tomatoes, exerted an anti-inflammatory effect modulating mitochondrial enzymes. Altogether, these findings support the notion that several positive effects of MedDiet can be mediated by a modulation in mitochondrial function indicating the necessity of further studies in human beings for finally confirming these findings.
    Keywords:  Dementia; Inflammation; Mediterranean diet; Metabolic syndrome; Mitochondria; Stress
    DOI:  https://doi.org/10.1016/j.exger.2023.112165
  12. Arch Gerontol Geriatr. 2023 Mar 31. pii: S0167-4943(23)00090-0. [Epub ahead of print]109 105011
    Skeletal muscle health: A key determinant of healthy aging.
    Liang-Kung Chen.
      
    Keywords:  Healthy aging; Muscle health; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.archger.2023.105011
  13. Geroscience. 2023 Apr 04.
    The transcription regulator ATF4 is a mediator of skeletal muscle aging.
    Matthew J Miller, George R Marcotte, Nathan Basisty, Cameron Wehrfritz, Zachary C Ryan, Matthew D Strub, Andrew T McKeen, Jennifer I Stern, Karl A Nath, Blake B Rasmussen, Andrew R Judge, Birgit Schilling, Scott M Ebert, Christopher M Adams.
      Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults.
    Keywords:  ATF4; Aging; Protein turnover; Sarcopenia; Skeletal muscle; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1007/s11357-023-00772-y
  14. Nat Rev Rheumatol. 2023 Apr 06.
    Mitochondrial fumarate implicated in inflammation.
    Sarah Onuora.
      
    DOI:  https://doi.org/10.1038/s41584-023-00963-z
  15. JACC Heart Fail. 2023 Apr;pii: S2213-1779(23)00078-1. [Epub ahead of print]11(4): 465-468
    Exercise Training in Heart Failure With Preserved Ejection Fraction: Is the Peripheral Vasculature Involved?
    Julio A Chirinos.
      
    Keywords:  arterial function; arterial stiffness; endothelium; exercise training; heart failure with preserved ejection fraction
    DOI:  https://doi.org/10.1016/j.jchf.2023.01.022
  16. Mol Med Rep. 2023 May;pii: 106. [Epub ahead of print]27(5):
    Inhibition of LPS‑induced NLRP3 inflammasome activation by stem cell‑conditioned culture media in human gingival epithelial cells.
    Hong Li, Licong Sun, Yuesen Wang.
      Interleukin (IL)‑1β is a pathogenic factor associated with the destruction of periodontal tissue in periodontitis. IL‑1β processing is regulated by cytosolic machinery known as the inflammasome. Porphyromonas gingivalis infection and lipopolysaccharide (LPS) have an important role in the destruction of periodontal tissue in periodontitis. P. gingivalis infection and LPS have been reported to activate the NOD‑like receptor family pyrin domain‑containing protein 3 (NLRP3) inflammasome in human oral cells. Stem cell therapy exhibits anti‑inflammatory effects and stem cell‑conditioned culture media (SCM) shows similar beneficial effects. The present study tested the hypothesis that SCM inhibits activation of the inflammasome and protects human gingival epithelial cells (GECs) against LPS‑induced inflammatory damage. Human GECs were treated with or without LPS plus SCM or control cell media. NLPR3 inflammasome components and inflammatory factors were measured by western blotting and immunofluorescence. The present study revealed that LPS induced an increase in the expression of inflammasome components, NLRP3, apoptosis‑associated speck‑like protein containing a caspase recruitment domain (ASC) and caspase‑1. Co‑immunoprecipitation revealed increased binding of NLRP3 and ASC, and immunofluorescence showed an increased co‑localization of ASC and caspase‑1, suggesting that LPS stimulated assembly of the NLRP3 inflammasome. SCM inhibited the overexpression and assembly of NLRP3 inflammasome components induced by LPS. Furthermore, SCM blocked the increase in IL‑1β production induced by LPS and inhibited the translocation of the inflammatory factor, NF‑κB, into the nuclei. Consequently, SCM protected cells against LPS‑induced damage, as suggested by the recovery of disturbed E‑cadherin staining pattern, which indicates a disruption in epithelial integrity. In conclusion, treatment with SCM may attenuate LPS‑induced inflammatory damage in human GECs via inhibition of NLRP3 inflammasome activation, suggesting a potential therapeutic use for SCM.
    Keywords:  E‑cadherin; NF‑κB; caspase‑1; inflammation; interleukin‑1β
    DOI:  https://doi.org/10.3892/mmr.2023.12993
  17. Physiol Rep. 2023 Apr;11(7): e15632
    TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.
    Rikuhide Koma, Tsubasa Shibaguchi, Yuhei Araiso, Tatsuya Yamada, Yudai Nonaka, Thomas Jue, Kazumi Masuda.
      Recently, we found that myoglobin (Mb) localizes in both the cytosol and mitochondrial intermembrane space in rodent skeletal muscle. Most proteins of the intermembrane space pass through the outer mitochondrial membrane via the translocase of the outer membrane (TOM) complex. However, whether the TOM complex imports Mb remains unknown. The purpose of this study was to investigate the involvement of the TOM complex in Mb import into the mitochondria. A proteinase K protection assay of mitochondria from C2C12 myotubes confirmed that Mb integrated into the mitochondria. An immunoprecipitation assay verified the interaction of Mb and TOM complex receptors (Tom20, Tom70) in isolated mitochondria. The assay showed a clear interaction of Mb with Tom20 and Tom70. A knockdown experiment using siRNA for TOM complex receptors (Tom20, Tom70) and TOM complex channel (Tom40) did not alter the amount of Mb expression in the mitochondrial fraction. These results suggested that Mb does not necessarily require the TOM complex for mitochondrial import of Mb. Although the physiological role of Mb interactions with TOM complex receptors remains unclear, further studies are needed to clarify how Mb enters the mitochondria independently of the TOM complex.
    Keywords:  Tom20; Tom40; Tom70; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.15632
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