bims-kimdis 2022-08-14 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–08–14
seventeen papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Impact of Aging and Lifelong Exercise Training on Mitochondrial Function and Network Connectivity in Human Skeletal Muscle.
The short-chain fatty acid butyrate accelerates vascular calcification via regulation of histone deacetylases and NF-κB signaling.
Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review.
The Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease.
Gaining insight into the role of FoxO1 in the progression of disuse-induced skeletal muscle atrophy.
Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
Resolvin D3 improves the impairment of insulin signaling in skeletal muscle and nonalcoholic fatty liver disease through AMPK/autophagy-associated attenuation of ER stress.
Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
Oligosaccharide and short-chain fatty acid: A double-edged sword in obese mice by regulating food intake and fat synthesis.
Short-Chain Carbon Sources: Exploiting Pleiotropic Effects for Heart Failure Therapy.
Effect of processing on the anti-inflammatory efficacy of cocoa in a high fat diet-induced mouse model of obesity.
Location matters: hexokinase 1 in glucose metabolism and inflammation.
Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis.
Skeletal muscle macrophage ablation in mice.
Lipid droplets promote efficient mitophagy.
Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases.
Keeping the beat against time: Mitochondrial fitness in the aging heart.

J Gerontol A Biol Sci Med Sci. 2022 Aug 12. pii: glac164. [Epub ahead of print]

Impact of Aging and Lifelong Exercise Training on Mitochondrial Function and Network Connectivity in Human Skeletal Muscle.

Stine Ringholm, Anders Gudiksen, Jens Frey Halling, Albina Qoqaj, Philip Meizner Rasmussen, Clara Prats, Peter Plomgaard, Henriette Pilegaard.

  Aging is associated with metabolic decline and reduction in mitochondrial function in skeletal muscle which can be delayed by physical activity. Moreover, exercise training has been shown to prevent age-associated decline in mitochondrial function and fragmentation of the mitochondrial network in mouse skeletal muscle. However, whether lifelong endurance exercise training exerts the same effects in human skeletal muscle is still not clear. Therefore, the aim of the present study was to examine the effect of volume-dependent lifelong endurance exercise training on mitochondrial function and network connectivity in older human skeletal muscle. Skeletal muscle complex I+II-linked mitochondrial respiration per tissue mass was higher, but intrinsic complex I+II-linked mitochondrial respiration was lower in highly trained older than in young untrained, older untrained and older moderately trained men. Mitochondrial volume and connectivity were higher in highly trained older than in untrained and moderately trained older subjects. Furthermore, protein content of the ADP/ATP exchangers ANT1 + 2 and VDAC was higher and of the mitophagic marker Parkin lower in skeletal muscle from the highly trained older than from untrained and moderately trained older subjects. In contrast, H2O2 emission in skeletal muscle was not affected by either age or exercise training, but SOD2 protein content was higher in highly trained older than in untrained and moderately trained older subjects. This suggests that healthy aging does not induce oxidative stress or mitochondrial network fragmentation in human skeletal muscle, but high-volume exercise training increases mitochondrial volume and network connectivity, thereby increasing oxidative capacity in older human skeletal muscle.

Keywords:  Mitochondria; mitophagy; physical activity; respirometry; skeletal muscle

DOI:  https://doi.org/10.1093/gerona/glac164
Vascul Pharmacol. 2022 Aug 08. pii: S1537-1891(22)00145-8. [Epub ahead of print] 107096

The short-chain fatty acid butyrate accelerates vascular calcification via regulation of histone deacetylases and NF-κB signaling.

Hui Zhong, Hongjiao Yu, Jiaxin Chen, Simon Wing Fai Mok, Xiao Tan, Bohou Zhao, Shengping He, Lan Lan, Xiaodong Fu, Guojun Chen, Dongxing Zhu.

  Recent studies have shown that short-chain fatty acids (SCFAs), primarily acetate, propionate and butyrate, play a crucial role in the pathogenesis of cardiovascular disease. Whether SCFAs regulate vascular calcification, a common pathological change in cardiovascular tissues, remains unclear. This study aimed to investigate the potential role of SCFAs in vascular calcification. Using cellular and animal models of vascular calcification, we showed that butyrate significantly enhanced high phosphate (Pi)-induced calcification and osteogenic transition of vascular smooth muscle cells (VSMC) in vitro, whereas acetate and propionate had no effects. Subsequent studies confirmed that butyrate significantly promoted high Pi-induced aortic ring calcification ex vivo and high dose vitamin D3 (vD3)-induced mouse vascular calcification in vivo. Mechanistically, butyrate significantly inhibited histone deacetylase (HDAC) expression in VSMCs, and a pan HDAC inhibitor Trichostatin A showed similar inductive effects on calcification and osteogenic transition of VSMCs to butyrate. In addition, the SCFA sensing receptors Gpr41 and Gpr109a were primarily expressed by VSMCs, and butyrate induced the rapid activation of NF-κB, Wnt and Akt signaling in VSMCs. Intriguingly, the NF-κB inhibitor SC75741 significantly attenuated butyrate-induced calcification and the osteogenic gene Msx2 expression in VSMCs. We showed that knockdown of Gpr41 but not Gpr109a attenuated butyrate-induced VSMC calcification. This study reveals that butyrate accelerates vascular calcification via its dual effects on HDAC inhibition and NF-κB activation. Our data provide novel insights into the role of microbe-host interaction in vascular calcification, and may have implications for the development of potential therapy for vascular calcification.

Keywords:  Histone deacetylase; NF-κB signaling; The SCFA butyrate; Vascular calcification; Vascular smooth muscle cells

DOI:  https://doi.org/10.1016/j.vph.2022.107096
Nutrients. 2022 Jul 30. pii: 3145. [Epub ahead of print]14(15):

Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review.

Rossella Tozzi, Fiammetta Cipriani, Davide Masi, Sabrina Basciani, Mikiko Watanabe, Carla Lubrano, Lucio Gnessi, Stefania Mariani.

  Ketone bodies (KBs) and Sirtuin-1 (SIRT1) have received increasing attention over the past two decades given their pivotal function in a variety of biological contexts, including transcriptional regulation, cell cycle progression, inflammation, metabolism, neurological and cardiovascular physiology, and cancer. As a consequence, the modulation of KBs and SIRT1 is considered a promising therapeutic option for many diseases. The direct regulation of gene expression can occur in vivo through histone modifications mediated by both SIRT1 and KBs during fasting or low-carbohydrate diets, and dietary metabolites may contribute to epigenetic regulation, leading to greater genomic plasticity. In this review, we provide an updated overview of the epigenetic interactions between KBs and SIRT1, with a particular glance at their central, synergistic roles for metabolic health.

Keywords:  NAFLD; SIRT1; epigenetic regulators; ketogenic diet; ketone bodies; obesity; visceral fat; β-OH-butyrate

DOI:  https://doi.org/10.3390/nu14153145
Nutrients. 2022 Jul 29. pii: 3136. [Epub ahead of print]14(15):

The Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease.

Lauren N Woodie, Kaan T Oral, Brianna M Krusen, Mitchell A Lazar.

  Obesity and other metabolic diseases are major public health issues that are particularly prevalent in industrialized societies where circadian rhythmicity is disturbed by shift work, jet lag, and/or social obligations. In mammals, daylight entrains the hypothalamic suprachiasmatic nucleus (SCN) to a ≈24 h cycle by initiating a transcription/translation feedback loop (TTFL) of molecular clock genes. The downstream impacts of the TTFL on clock-controlled genes allow the SCN to set the rhythm for the majority of physiological, metabolic, and behavioral processes. The TTFL, however, is ubiquitous and oscillates in tissues throughout the body. Tissues outside of the SCN are entrained to other signals, such as fed/fasting state, rather than light input. This system requires a considerable amount of biological flexibility as it functions to maintain homeostasis across varying conditions contained within a 24 h day. In the face of either circadian disruption (e.g., jet lag and shift work) or an obesity-induced decrease in metabolic flexibility, this finely tuned mechanism breaks down. Indeed, both human and rodent studies have found that obesity and metabolic disease develop when endogenous circadian pacing is at odds with the external cues. In the following review, we will delve into what is known on the circadian rhythmicity of nutrient metabolism and discuss obesity as a circadian disease.

Keywords:  circadian rhythms; metabolism; molecular clock; obesity

DOI:  https://doi.org/10.3390/nu14153136
Adv Biol Regul. 2022 Jul 31. pii: S2212-4926(22)00043-4. [Epub ahead of print]85 100903

Gaining insight into the role of FoxO1 in the progression of disuse-induced skeletal muscle atrophy.

Natalia Vilchinskaya, Erzhena Altaeva, Yulia Lomonosova.

  Expression of FoxO transcription factors increases during certain forms of atrophy. In a dephosphorylated state, FoxOs participate in ubiquitin-mediated proteasomal degradation through the transcriptional activation of E3-ubiquitin ligases such as MAFbx/atrogin-1 and MuRF1. There is exhaustive research demonstrating that FoxO3a is sufficient to induce MAFbx/atrogin-1 and MuRF-1 expressions. In contrast, the data are conflicting on the requirement of FoxO1 signaling in the activation of the E3-ubiquitin ligases. Moreover, no reports currently exist on the particular role of FoxO1 in the molecular mechanisms involved in the progression of physiological muscle wasting. Here, we have applied the most extensively used rodent model of microgravity/functional unloading to stimulate disuse-induced skeletal muscle atrophy such as rat hindlimb suspension (HS). We showed that inhibition of FoxO1 activity by a selective inhibitor AS1842856 completely reversed an increase in expression of MuRF-1, but not MAFbx/atrogin-1, observed upon HS. Furthermore, we demonstrated that FoxO1 induced upregulation of another E3-ubiquitin-ligase of a MuRF protein family MuRF-2 in skeletal muscle subjected to disuse. Prevention of the MuRF increase upon HS impeded upregulation of transcript expression of a negative regulator of NFATc1 pathway calsarcin-2, which was associated with a partial reversion of MyHC-IId/x and MyHC-IIb mRNA expressions. Importantly, FoxO1 inhibition induced a marked increase in p70S6k phosphorylation, an important stage in the initiation of protein translation, concomitant with the restoration of global protein synthesis in the skeletal muscle of the HS rats. Examination of eIF3f expression and the eEF2k/eEF2 pathway, other factors controlling translation initiation and elongation respectively, did not reveal any impact of FoxO1 on their activity. Lastly, we observed a decrease in transcript levels of Sesn3, but not Sesn1 and Sesn2, upon disuse, which was completely reversed by FoxO1 inhibition. These data demonstrate that FoxO1 signaling contributes to the development of disuse-induced skeletal muscle atrophy, including slow to fast MyHC isoform shift, mostly through upregulation of MuRF-1 and MuRF-2 expression. Furthermore, FoxO1 inhibition is required to recover Sesn3 mRNA expression in atrophic conditions, which likely contributes to the enhanced p70S6k activity and restoration of the protein synthesis rate.

Keywords:  E3-ubiquitin ligases; Forkhead box O 1; Myosin heavy chains; Protein synthesis; Sestrins; Skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.jbior.2022.100903
Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00129-6. [Epub ahead of print] 101560

Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.

Patrick M Schaefer, Jessica Huang, Arrienne Butic, Caroline Perry, Tal Yardeni, Wendy Tan, Ryan Morrow, Joseph A Baur, Douglas C Wallace.

   OBJECTIVE: Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.
METHODS: This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.
RESULTS: We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.
CONCLUSION: Increasing NAD + levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.

Keywords:  Exercise; Mitochondrial disorder; NAD(+)/NADH; Nicotinamide riboside

DOI:  https://doi.org/10.1016/j.molmet.2022.101560
Biochem Pharmacol. 2022 Aug 07. pii: S0006-2952(22)00297-0. [Epub ahead of print] 115203

Resolvin D3 improves the impairment of insulin signaling in skeletal muscle and nonalcoholic fatty liver disease through AMPK/autophagy-associated attenuation of ER stress.

Heeseung Oh, Wonjun Cho, A M Abd El-Aty, Cemil Bayram, Ji Hoon Jeong, Tae Woo Jung.

  Resolvin D3 (RD3), an endogenous lipid mediator derived from omega-3 fatty acids, has been documented to attenuate inflammation in various disease models. Although it has been reported that omega-3 fatty acids attenuate metabolic disorders, the roles of RD3 in insulin signaling in skeletal muscle and hepatic lipid metabolism remain unclear. In the current study, we examined the role of RD3 in skeletal muscle insulin resistance and hepatic steatosis using in vitro and in vivo obesity models. In mouse primary hepatocytes, RD3 treatment reduced lipid accumulation and the production of lipogenic proteins (processed SREBP1 and SCD1) while improving insulin signaling in C2C12 myocytes. Furthermore, RD3 treatment ameliorated palmitate-induced ER stress markers (phospho-eIF2α and CHOP) in mouse primary hepatocytes and C2C12 myocytes. Treatment with RD3 increased phospho-AMPK expression and autophagy markers (LC3 conversion, p62 degradation, and autophagosome formation). AMPK siRNA or 3-MA reduced the effects of RD3 on C2C12 myocytes and mouse primary hepatocytes treated with palmitate. Finally, we confirmed the therapeutic effects of RD3 on skeletal muscle insulin resistance and hepatic lipid metabolism in high-fat diet (HFD)-fed mice. In vivo transfection-mediated suppression of AMPK restored all these changes in animal models. The results of the present study suggest that RD3 alleviates insulin resistance in skeletal muscle and hepatic steatosis via AMPK/autophagy signaling and provides an effective and safe therapeutic approach for treating metabolic disorders, including insulin resistance, type 2 diabetes, and NAFLD.

Keywords:  AMPK; Autophagy; ER stress; Insulin resistance; NAFLD; Resolvin D3

DOI:  https://doi.org/10.1016/j.bcp.2022.115203
Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041261. [Epub ahead of print]

Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.

Ana Paula Arruda, Güneş Parlakgül.

The endoplasmic reticulum (ER) is a key organelle involved in the regulation of lipid and glucose metabolism, proteostasis, Ca2+ signaling, and detoxification. The structural organization of the ER is very dynamic and complex, with distinct subdomains such as the nuclear envelope and the peripheral ER organized into ER sheets and tubules. ER also forms physical contact sites with all other cellular organelles and with the plasma membrane. Both form and function of the ER are highly adaptive, with a potent capacity to respond to transient changes in environmental cues such as nutritional fluctuations. However, under obesity-induced chronic stress, the ER fails to adapt, leading to ER dysfunction and the development of metabolic pathologies such as insulin resistance and fatty liver disease. Here, we discuss how the remodeling of ER structure and contact sites with other organelles results in diversification of metabolic function and how perturbations to this structural flexibility by chronic overnutrition contribute to ER dysfunction and metabolic pathologies in obesity.

DOI: https://doi.org/10.1101/cshperspect.a041261
Food Res Int. 2022 Sep;pii: S0963-9969(22)00677-9. [Epub ahead of print]159 111619

Oligosaccharide and short-chain fatty acid: A double-edged sword in obese mice by regulating food intake and fat synthesis.

Kaiyang Chen, Meimei Hu, Ming Tang, Congcong Gao, Haikuan Wang, Shuli Man, Fuping Lu.

  Dietary fiber has been used to prevent obesity by regulating the intestinal flora and promoting the production of short-chain fatty acids (SCFAs). However, it is insufficient to conclude the decisive role of microbiota and SCFAs by adding oligosaccharides to foods without caloric balance. In this study, the effects of oligosaccharides and their regulated microflora on the development of obesity in mice were studied by designing a high-fat diet with equal calories but different contents of oligosaccharides. Isocaloric diets demonstrated that appropriate rather than excess oligosaccharides prevent obesity by regulating appetite. Such an appetite was inhibited by oligosaccharides but promoted by SCFAs. Furthermore, promoted appetite was tightly related to decreased insulin and increased acyl-CoA binding protein, which was correlated with SCFA-induced fat degradation. Interestingly, drinking butyrate alleviated obesity even with higher calorie intake. Molecular docking demonstrated that conversion of butyrate to butyryl-CoA converted from butyrate, as a structural analog of acetyl-CoA, inhibits the activity of acetyl-CoA carboxylase. Together, these findings demonstrate that fermentable fiber supplements may have limits in obesity treatment, and we provide possible obesity therapeutic targets that inhibit bacterial fermentation or increase the ratio of butyrate/acetate.

Keywords:  Acetyl-CoA carboxylase; Appetite; Fat synthesis; Hormone; Obesity; Oligose; SCFA

DOI:  https://doi.org/10.1016/j.foodres.2022.111619
JACC Basic Transl Sci. 2022 Jul;7(7): 730-742

Short-Chain Carbon Sources: Exploiting Pleiotropic Effects for Heart Failure Therapy.

Azariyas A Challa, E Douglas Lewandowski.

  Heart failure (HF) remains the leading cause of morbidity and mortality in the developed world, highlighting the urgent need for novel, effective therapeutics. Recent studies support the proposition that improved myocardial energetics as a result of ketone body (KB) oxidation may account for the intriguing beneficial effects of sodium-glucose cotransporter-2 inhibitors in patients with HF. Similar small molecules, short-chain fatty acids (SCFAs) are now realized to be preferentially oxidized over KBs in failing hearts, contradicting the notion of KBs as a rescue "superfuel." In addition to KBs and SCFAs being alternative fuels, both exert a wide array of nonmetabolic functions, including molecular signaling and epigenetics and as effectors of inflammation and immunity, blood pressure regulation, and oxidative stress. In this review, the authors present a perspective supported by new evidence that the metabolic and unique nonmetabolic activities of KBs and SCFAs hold promise for treatment of patients with HF with reduced ejection fraction and those with HF with preserved ejection fraction.

Keywords:  BP, blood pressure; CPT1, carnitine palmitoyltransferase I; CoA, coenzyme A; FFAR, free fatty acid receptor; GPR, G protein–coupled receptor; HF, heart failure; HFpEF; HFpEF, heart failure with preserved ejection fraction; HFrEF; KB, ketone body; LCFA, long-chain fatty acid; SCFA, short-chain fatty acid; SGLT2, sodium-glucose cotransporter-2; heart failure; ketones; short-chain fatty acids; β-HB, β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jacbts.2021.12.010
J Nutr Biochem. 2022 Aug 04. pii: S0955-2863(22)00185-1. [Epub ahead of print] 109117

Effect of processing on the anti-inflammatory efficacy of cocoa in a high fat diet-induced mouse model of obesity.

Daphne K Weikart, Vijaya V Indukuri, Kathryn C Racine, Kiana M Coleman, Jasna Kovac, Darrell W Cockburn, Helene Hopfer, Andrew P Neilson, Joshua D Lambert.

  Obesity causes inflammation which may lead to development of co-morbidities like cardiovascular diseases. Cocoa is a popular food ingredient that has been shown to mitigate obesity and inflammation in preclinical models. Cocoa typically undergoes fermentation and roasting prior to consumption, which can affect the polyphenol content in cocoa. The aim of this study was to compare the effect of fermentation and roasting protocols on the ability of cocoa to mitigate obesity, gut barrier dysfunction, and chronic inflammation in high fat (HF)-fed, obese C57BL/6J mice. We found that treatment of mice with 80 mg/g dietary cocoa powder for 8 weeks reduced rate of body weight gain in both male and female mice (46 - 57%), regardless of fermentation and roasting protocol. Colonic length was increased (11 - 24%) and gut permeability was reduced (48 - 79%) by cocoa supplementation. Analysis of the cecal microbiome showed that cocoa, regardless of fermentation and roasting protocol, reduced the ratio of Firmicutes to Bacteroidetes. Multivariate statistical analysis of markers of inflammation and body weight data showed sex differences in the effect of both the HF diet as well as cocoa supplementation. Based on this data there was strong protective efficacy from cocoa supplementation especially for the more processed cocoa samples. Overall, this study shows that anti-obesity and anti-inflammatory efficacy of cocoa is resilient to changes in polyphenol content and composition induced by fermentation or roasting. Further, this study shows that although cocoa has beneficial effects in both males and females, there are significant sex differences.

Keywords:  Cocoa; fermentation; inflammation; obesity; roasting; sex differences

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109117
Trends Endocrinol Metab. 2022 Aug 08. pii: S1043-2760(22)00140-0. [Epub ahead of print]

Location matters: hexokinase 1 in glucose metabolism and inflammation.

Sivaraj M Sundaram, Luke A Doughty, Michael W Sereda.

  Hexokinase (HK)-1 mitochondrial-binding mechanisms and consequential physiological relevance remain unclear. Recently, De Jesus et al. studied myeloid cells with HK1 carrying mutated mitochondrial-binding domains (MBDs) and provided evidence that HK1 localization controls glucose metabolic fate. Increases in cytosolic HK1 may also contribute to the inflammation associated with diabetes and aging.

Keywords:  aging; deacetylation; diabetes; glucose metabolism; inflammation; nitrosylation

DOI:  https://doi.org/10.1016/j.tem.2022.07.005
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Aug 04. pii: S1388-1981(22)00099-3. [Epub ahead of print]1867(11): 159209

Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis.

Curtis C Hughey, Patrycja Puchalska, Peter A Crawford.

  The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing globally. NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). NASH is the pathological form of the disease characterized by liver steatosis, inflammation, cell injury, and fibrosis. A fundamental contributor to NASH is the imbalance between lipid accretion and disposal. The accumulation of liver lipids precipitates lipotoxicity and the inflammatory contributions to disease progression. This review defines the role of dysregulated of lipid disposal in NAFLD pathophysiology. The characteristic changes in mitochondrial oxidative metabolism pathways and the factors promoting these changes across the spectrum of NAFLD severity are detailed. This includes pathway-specific and integrative perturbations in mitochondrial β-oxidation, citric acid cycle flux, oxidative phosphorylation, and ketogenesis. Moreover, well-recognized and emerging mechanisms through which dysregulated mitochondrial oxidative metabolism mediates inflammation, fibrosis, and disease progression are highlighted.

Keywords:  Citric acid cycle; Inflammation; Ketogenesis; Lipid metabolism; Non-alcoholic steatohepatitis; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.bbalip.2022.159209
J Immunol Methods. 2022 Aug 03. pii: S0022-1759(22)00116-8. [Epub ahead of print] 113329

Skeletal muscle macrophage ablation in mice.

Jennifer T W Krall, Kevin W Gibbs, Lanazha Belfield, Chun Liu, Lina Purcell, Joseph J Bivona, Matthew E Poynter, Renee D Stapleton, Michael J Toth, D Clark Files.

  Macrophages are important mediators of skeletal muscle function in both healthy and diseased states. In vivo specific depletion of macrophages provides an experimental method to understand physiological and pathophysiological effects of macrophages. Systemic depletion of macrophages can deplete skeletal muscle macrophages but also alters systemic inflammatory responses and metabolism, which confounds the muscle specific effects of macrophage depletion. The primary aim of this manuscript is to evaluate two methods of murine intramuscular macrophage depletion in an acute lung injury-associated indirect skeletal muscle wasting mouse model. Adult C57BL/6 (WT) and Macrophage Fas-Induced Apoptosis (MaFIA, C57BL/6-Tg) mice received clodronate liposomes or the dimerization drug AP20187 through intramuscular injection of the tibialis anterior muscle compartment, respectively. Vehicle control was injected in the contralateral muscle. We demonstrate intramuscular AP20187 in the MaFIA mouse depletes macrophages but causes an infiltration of CD45 intermediate neutrophils. In contrast, intramuscular clodronate liposomes successfully depletes macrophages without an associated increase in CD45 intermediate cells. In conclusion, intramuscular clodronate is effective for selective depletion of muscle macrophages without eliciting acute inflammation seen with AP20187 in MaFIA mice. This technique is an important tool to study the functional roles of macrophages in skeletal muscle.

Keywords:  Clodronate liposomes; Conditional macrophage depletion; Inflammation; Skeletal muscle; Transgenic mouse model

DOI:  https://doi.org/10.1016/j.jim.2022.113329
Autophagy. 2022 Aug 08. 1-2

Lipid droplets promote efficient mitophagy.

Maeve Long, Thomas G McWilliams.

  Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.

Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy

DOI:  https://doi.org/10.1080/15548627.2022.2089956
Ageing Res Rev. 2022 Aug 04. pii: S1568-1637(22)00148-9. [Epub ahead of print]81 101706

Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases.

Tongtong Hu, Qingqing Wu, Qi Yao, Kebing Jiang, Jiabin Yu, Qizhu Tang.

  Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, and fatty acid metabolism has been well studied. Short-chain fatty acids (SCFAs) have been less discussed than long-chain fatty acids (LCFAs) in CVDs. However, increasing evidence indicates the importance of SCFAs in regulating cardiac function. Here, we summarize the current understanding of SCFAs in hypertension, ischaemic reperfusion, myocardial infarction, atherosclerosis and heart failure. Most SCFAs exert positive effects in regulating related diseases. Butyrate and propionate can reduce blood pressure, improve I/R injury and decrease the risk of coronary artery disease (CAD) and atherosclerosis. Acetate can also play a positive role in regulating hypertension and preventing atherosclerosis, and malonate can improve cardiac function after MI. They affect these diseases by regulating inflammation, the immune system and related G protein-coupled receptors, with multiple neurohumoural regulation participation. In contrast, succinate can accelerate IR injury, increasing mitochondrial ROS production. SCFAs ultimately affect the regulation of different pathophysiological processes in heart failure. Here, we clarified the importance of short-chain fatty acids in the cardiovascular system and their multiple effects in various pathophysiological processes, providing new insights into their promising clinical application. More research should be conducted to further elucidate the underlying mechanism and different effects of single or multiple SCFA supplementation on the cardiovascular system.

Keywords:  Atherosclerosis; Heart failure; Hypertension; Myocardial infarction; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.arr.2022.101706
Front Aging. 2022 ;3 951417

Keeping the beat against time: Mitochondrial fitness in the aging heart.

Arielys Mendoza, Jason Karch.

  The process of aging strongly correlates with maladaptive architectural, mechanical, and biochemical alterations that contribute to the decline in cardiac function. Consequently, aging is a major risk factor for the development of heart disease, the leading cause of death in the developed world. In this review, we will summarize the classic and recently uncovered pathological changes within the aged heart with an emphasis on the mitochondria. Specifically, we describe the metabolic changes that occur in the aging heart as well as the loss of mitochondrial fitness and function and how these factors contribute to the decline in cardiomyocyte number. In addition, we highlight recent pharmacological, genetic, or behavioral therapeutic intervention advancements that may alleviate age-related cardiac decline.

Keywords:  ROS; autophagy; cell death; metabolism; mitochondria; mitochondrial biogenesis; mitochondrial fitness; mitophagy

DOI:  https://doi.org/10.3389/fragi.2022.951417