bims-mimcad 2024-02-18 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024‒02‒18
thirteen papers selected by
Henver Brunetta, University of Guelph

Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.
Insulin at the intersection of thermoregulation and glucose homeostasis.
Functional Impact of Alternative Metabolic Substrates in Failing Human Cardiomyocytes.
Chronic exercise improves hepatic acylcarnitine handling.
Endurance exercise preconditioning alleviates ferroptosis induced by doxorubicin-induced cardiotoxicity through mitochondrial superoxide-dependent AMPKα2 activation.
Connexin43 in mesenchymal lineage cells regulates body adiposity and energy metabolism in mice.
Decreased sarcoplasmic reticulum phospholipids in human skeletal muscle are associated with metabolic syndrome.
Cardiac reverse remodelling in a mouse model with many phenotypical features of heart failure with preserved ejection fraction: effects of modifying lifestyle.
Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.
HNF4α ubiquitination mediated by Peli1 impairs FAO and accelerates pressure overload-induced myocardial hypertrophy.
FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a.
Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.
Bed-rest and exercise remobilization: Concurrent adaptations in muscle glucose and protein metabolism.

Am J Physiol Endocrinol Metab. 2024 Feb 14.

Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.

Michael R Martino, Mohammad Habibi, Daniel Ferguson, Rita T Brookheart, John P Thyfault, Gretchen A Meyer, Louise Lantier, Curtis C Hughey, Brian N Finck.

  Exercise robustly increases the glucose demands of skeletal muscle. This demand is met not only by muscle glycogenolysis, but also by accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting gluconeogenic efficiency and capacity on exercise performance by deleting hepatic mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or post-exercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in liver (DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of ²H/¹³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. The decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan crosstalk during exercise as described by the Cahill and Cori cycles.

Keywords:  alanine transaminase; exercise; gluconeogenesis; mitochondrial pyruvate carrier

DOI:  https://doi.org/10.1152/ajpendo.00258.2023
Mol Metab. 2024 Feb 13. pii: S2212-8778(24)00032-2. [Epub ahead of print] 101901

Insulin at the intersection of thermoregulation and glucose homeostasis.

Nathan C Winn, Michael W Schleh, Jamie N Garcia, Louise Lantier, Owen P McGuinness, Joslin A Blair, Alyssa H Hasty, David H Wasserman.

Mammals are protected from changes in environmental temperature by altering energetic processes that modify heat production. Insulin is the dominant stimulus of glucose uptake and metabolism, which are fundamental for thermogenic processes. The purpose of this work was to determine the interaction of ambient temperature induced changes in energy expenditure (EE) on the insulin sensitivity of glucose fluxes. Short-term and adaptive responses to thermoneutral temperature (TN, ∼28 °C) and room (laboratory) temperature (RT, ∼22 °C) were studied in mice. This range of temperature does not cause detectable changes in circulating catecholamines or shivering and postabsorptive glucose homeostasis is maintained. We tested the hypothesis that a decrease in EE that occurs with TN causes insulin resistance and that this reduction in insulin action and EE is reversed upon short term (<12h) transition to RT. Insulin-stimulated glucose disposal (Rd) and tissue-specific glucose metabolic index were assessed combining isotopic tracers with hyperinsulinemic-euglycemic clamps. EE and insulin-stimulated Rd are both decreased (∼50%) in TN-adapted vs RT-adapted mice. When RT-adapted mice are switched to TN, EE rapidly decreases and Rd is reduced by ∼50%. TN-adapted mice switched to RT exhibit a rapid increase in EE, but whole-body insulin-stimulated Rd remains at the low rates of TN-adapted mice. In contrast, whole body glycolytic flux rose with EE. This higher EE occurs without increasing glucose uptake from the blood, but rather by diverting glucose from glucose storage to glycolysis. In addition to adaptations in insulin action, 'insulin-independent' glucose uptake in brown fat is exquisitely sensitive to thermoregulation. These results show that insulin action adjusts to non-stressful changes in ambient temperature to contribute to the support of body temperature homeostasis without compromising glucose homeostasis.

DOI: https://doi.org/10.1016/j.molmet.2024.101901
JACC Basic Transl Sci. 2024 Jan;9(1): 1-15

Functional Impact of Alternative Metabolic Substrates in Failing Human Cardiomyocytes.

Alexia Vite, Timothy R Matsuura, Kenneth C Bedi, Emily L Flam, Zoltan Arany, Daniel P Kelly, Kenneth B Margulies.

  Recent studies suggest that metabolic dysregulation in patients with heart failure might contribute to myocardial contractile dysfunction. To understand the correlation between function and energy metabolism, we studied the impact of different fuel substrates on human nonfailing or failing cardiomyocytes. Consistent with the concept of metabolic flexibility, nonfailing myocytes exhibited excellent contractility in all fuels provided. However, impaired contractility was observed in failing myocytes when carbohydrates alone were used but was improved when additional substrates were added. This study demonstrates the functional significance of fuel utilization shifts in failing human cardiomyocytes.

Keywords:  carbohydrates, contractility; free fatty acids; heart failure; metabolic flexibility; metabolic fuel utilization; tissue metabolites

DOI:  https://doi.org/10.1016/j.jacbts.2023.07.009
iScience. 2024 Mar 15. 27(3): 109083

Chronic exercise improves hepatic acylcarnitine handling.

Diego Hernández-Saavedra, J Matthew Hinkley, Lisa A Baer, Kelsey M Pinckard, Pablo Vidal, Shinsuke Nirengi, Andrea M Brennan, Emily Y Chen, Niven R Narain, Valerie Bussberg, Vladimir V Tolstikov, Michael A Kiebish, Christina Markunas, Olga Ilkayeva, Bret H Goodpaster, Christopher B Newgard, Laurie J Goodyear, Paul M Coen, Kristin I Stanford.

  Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial β-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Keywords:  Cell biology; Health sciences; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109083
Redox Biol. 2024 Feb 08. pii: S2213-2317(24)00055-7. [Epub ahead of print]70 103079

Endurance exercise preconditioning alleviates ferroptosis induced by doxorubicin-induced cardiotoxicity through mitochondrial superoxide-dependent AMPKα2 activation.

Liang Wang, Yang Qiao, Jingzhi Yu, Qihao Wang, Xinyu Wu, Qiqi Cao, Zeyu Zhang, Zhen Feng, Huan He.

  Doxorubicin-induced cardiotoxicity (DIC) adversely impacts patients' long-term health and quality of life. Its underlying mechanism is complex, involving regulatory cell death mechanisms, such as ferroptosis and autophagy. Moreover, it is a challenge faced by patients undergoing cardiac rehabilitation. Endurance exercise (E-Exe) preconditioning effectively counters DIC injury, potentially through the adenosine monophosphate-activated protein kinase (AMPK) pathway. However, detailed studies on this process's mechanisms are scarce. Here, E-Exe preconditioning and DIC models were established using mice and primary cultured adult mouse cardiomyocytes (PAMCs). Akin to ferrostatin-1 (ferroptosis inhibitor), rapamycin (autophagic inducer), and MitoTEMPO (mitochondrial free-radical scavenger), E-Exe preconditioning effectively alleviated Fe2+ accumulation and oxidative stress and improved energy metabolism and mitochondrial dysfunction in DIC injury, as demonstrated by multifunctional, enzymatic, and morphological indices. However, erastin (ferroptosis inducer), 3-methyladenine (autophagic inhibitor), adenovirus-mediated AMPKα2 downregulation, and AMPKα2 inhibition by compound C significantly diminished these effects, both in vivo and in vitro. The results suggest a non-traditional mechanism where E-Exe preconditioning, under mild mitochondrial reactive oxygen species generation, upregulates and phosphorylates AMPKα2, thereby enhancing mitochondrial complex I activity, activating adaptive autophagy, and improving myocardial tolerance to DIC injury. Overall, this study highlighted the pivotal role of mitochondria in myocardial DIC-induced ferroptosis and shows how E-Exe preconditioning activated AMPKα2 against myocardial DIC injury. This suggests that E-Exe preconditioning could be a viable strategy for patients undergoing cardiac rehabilitation.

Keywords:  AMP-Activated protein kinaseα2; Doxorubicin-induced cardiotoxicity; Endurance exercise; Ferroptosis; Mitochondria

DOI:  https://doi.org/10.1016/j.redox.2024.103079
JCI Insight. 2024 Feb 13. pii: e170016. [Epub ahead of print]

Connexin43 in mesenchymal lineage cells regulates body adiposity and energy metabolism in mice.

Seung-Yon Lee, Francesca Fontana, Toshifumi Sugatani, Ignacio Portales Castillo, Giulia Leanza, Ariella Coler-Reilly, Roberto Civitelli.

  Connexin43 (Cx43) is the most abundant gap junction protein present in the mesenchymal lineage. In mature adipocytes, Cx43 mediates white adipose tissue (WAT) "beiging" in response to cold exposure and maintains the mitochondrial integrity of brown adipose tissue (BAT). We found that genetic deletion of Gja1 (Cx43 gene) in cells that give rise to chondro-osteogenic and adipogenic precursors driven by the Dermo1/Twist2 promoter led to lower body adiposity and partial protection against the weight gain and metabolic syndrome induced by a high fat diet (HFD) in both sexes. These protective effects from obesogenic diet were related to increased locomotion, fuel utilization, energy expenditure, non-shivering thermogenesis, and better glucose tolerance in conditionally Gja1 ablated mice. Accordingly, Gja1 mutant mice exhibited reduced adipocyte hypertrophy, partially preserved insulin sensitivity, increased BAT lipolysis and decreased whitening under HFD. This metabolic phenotype was not reproduced with more restricted Gja1 ablation in differentiated adipocytes, suggesting that Cx43 in adipocyte progenitors or other targeted cells restrains energy expenditures and promotes fat accumulation. These results disclose an hitherto unknown action of Cx43 in adiposity, and offer a promising new pharmacologic target for improving metabolic balance in diabetes and obesity.

Keywords:  Adipose tissue; Adult stem cells; Metabolism; Obesity

DOI:  https://doi.org/10.1172/jci.insight.170016
J Lipid Res. 2024 Feb 12. pii: S0022-2275(24)00024-5. [Epub ahead of print] 100519

Decreased sarcoplasmic reticulum phospholipids in human skeletal muscle are associated with metabolic syndrome.

Samantha E Adamson, Sangeeta Adak, Max C Petersen, Dustin Higgins, Larry D Spears, Rong Mei Zhang, Andrea Cedeno, Alexis McKee, Aswathi Kumar, Sudhir Singh, Fong-Fu Hsu, Janet B McGill, Clay F Semenkovich.

  Metabolic syndrome affects more than one in three adults and is associated with increased risk of diabetes, cardiovascular disease, and all-cause mortality. Muscle insulin resistance is a major contributor to the development of the metabolic syndrome. Studies in mice have linked skeletal muscle sarcoplasmic reticulum (SR) phospholipid composition to sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity and insulin sensitivity. To determine if the presence of metabolic syndrome alters specific phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species in human sarcoplasmic reticulum (SR), we compared SR phospholipid composition in skeletal muscle from sedentary subjects with metabolic syndrome and sedentary control subjects without metabolic syndrome. Both total PC and total PE were significantly decreased in skeletal muscle SR of sedentary metabolic syndrome patients compared to sedentary controls, particularly in female participants, but there was no difference in the PC:PE ratio between groups. Total SR PC levels, but not total SR PE levels or PC:PE ratio, were significantly negatively correlated with BMI, waist circumference, total fat, visceral adipose tissue, triglycerides, fasting insulin and HOMA-IR. These findings are consistent with the existence of a relationship between skeletal muscle SR PC content and insulin resistance in humans.

Keywords:  diabetes; insulin resistance; muscle; phospholipids/phosphatidylcholine

DOI:  https://doi.org/10.1016/j.jlr.2024.100519
Am J Physiol Heart Circ Physiol. 2024 Feb 16.

Cardiac reverse remodelling in a mouse model with many phenotypical features of heart failure with preserved ejection fraction: effects of modifying lifestyle.

Mohamed Lamine Aidara, Elisabeth Walsh-Wilkinson, Sara-Ève Thibodeau, Emylie-Ann Labbé, Audrey Morin-Grandmont, Genevieve Gagnon, Dominique K Boudreau, Marie Arsenault, Yohan Bossé, Jacques Couet.

  Multiple factors cause heart failure with preserved ejection fraction (HFpEF) and involve various systems. HFpEF prevalence is rapidly rising, and its prognosis remains poor after the first hospitalization. Adopting a more active lifestyle has been shown to provide beneficial clinical outcomes for HFpEF patients. Using a two-hit HFpEF murine model, we studied cardiac reverse remodelling (RR) after stopping the causing stress and introducing voluntary exercise (VE). We checked in 2-month-old male and female C57Bl6/J mice the heart's response to angiotensin II (AngII; 1.5 mg/kg/day for 28 days) fed or not with a high-fat diet (HFD). Then, AngII and/or the HFD were stopped, and VE was started for an additional four weeks. AngII and AngII+HFD (metabolic-hypertensive stress or MHS) caused cardiac hypertrophy (CH) and myocardial fibrosis, left ventricular (LV) concentric remodelling, atrial enlargement, and reduced exercise capacity. HFD alone induced CH and LV concentric remodelling in female mice only. CH and LV concentric remodelling were reversed four weeks after stopping AngII, starting VE, and a low-fat diet. Left atrial enlargement and exercise capacity were improved but differed from controls. We performed bulk LV RNA sequencing and observed that MHS upregulated 58% of the differentially expressed genes (DEGs) compared to controls. In the RR group, compared to MHS animals, 60% of the DEGs were downregulated. In an HFpEF mouse model, we show that correcting hypertension, diet, and introducing exercise can lead to extensive cardiac reverse remodelling.

Keywords:  heart failure; mouse; myocardial recovery; reverse remodeling; sex differences

DOI:  https://doi.org/10.1152/ajpheart.00462.2023
bioRxiv. 2024 Feb 04. pii: 2024.02.01.577463. [Epub ahead of print]

Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.

Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.

The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury. We previously demonstrated that inhibiting the lactate exporter, monocarboxylate transporter 4 (MCT4), and re-directing pyruvate towards oxidation can blunt isoproterenol-induced hypertrophy. Based on this finding, we hypothesized that the same pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a critical role in determining myocardial salvage following injury. Post-I/R injury, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium following I/R injury. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the myocardium at risk of injury. We deployed a pharmacological strategy of MCT4 inhibition with a highly selective compound (VB124) at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (Δψ), and Ca 2+ , increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R injury. Altogether, our data suggest that normalizing the pyruvate-lactate metabolic axis via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury.GRAPHICAL ABSTRACT:

DOI: https://doi.org/10.1101/2024.02.01.577463
Cell Death Dis. 2024 Feb 12. 15(2): 135

HNF4α ubiquitination mediated by Peli1 impairs FAO and accelerates pressure overload-induced myocardial hypertrophy.

Yuxing Hou, Pengxi Shi, Haiyang Du, Chenghao Zhu, Chao Tang, Linli Que, Guoqing Zhu, Li Liu, Qi Chen, Chuanfu Li, Guoqiang Shao, Yuehua Li, Jiantao Li.

Impaired fatty acid oxidation (FAO) is a prominent feature of metabolic remodeling observed in pathological myocardial hypertrophy. Hepatocyte nuclear factor 4alpha (HNF4α) is closely associated with FAO in both cellular processes and disease conditions. Pellino 1 (Peli1), an E3 ligase containing a RING-like domain, plays a crucial role in catalyzing polyubiquitination of various substrates. In this study, we aimed to investigate the involvement of HNF4α and its ubiquitination, facilitated by Peli1, in FAO during pressure overload-induced cardiac hypertrophy. Peli1 systemic knockout mice (Peli1KO) display improved myocardial hypertrophy and cardiac function following transverse aortic constriction (TAC). RNA-seq analysis revealed that changes in gene expression related to lipid metabolism caused by TAC were reversed in Peli1KO mice. Importantly, both HNF4α and its downstream genes involved in FAO showed a significant increase in Peli1KO mice. We further used the antagonist BI6015 to inhibit HNF4α and delivered rAAV9-HNF4α to elevate myocardial HNF4α level, and confirmed that HNF4α inhibits the development of cardiac hypertrophy after TAC and is essential for the enhancement of FAO mediated by Peli1 knockout. In vitro experiments using BODIPY incorporation and FAO stress assay demonstrated that HNF4α enhances FAO in cardiomyocytes stimulated with angiotension II (Ang II), while Peli1 suppresses the effect of HNF4α. Mechanistically, immunoprecipitation and mass spectrometry analyses confirmed that Peli1 binds to HNF4α via its RING-like domain and promotes HNF4α ubiquitination at residues K307 and K309. These findings shed light on the underlying mechanisms contributing to impaired FAO and offer valuable insights into a promising therapeutic strategy for addressing pathological cardiac hypertrophy.

DOI: https://doi.org/10.1038/s41419-024-06470-7
Redox Biol. 2024 Feb 09. pii: S2213-2317(24)00057-0. [Epub ahead of print]70 103081

FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a.

Miyesaier Abudureyimu, Xuanming Luo, Lingling Jiang, Xuejuan Jin, Cuizhen Pan, Wei Yu, Junbo Ge, Yingmei Zhang, Jun Ren.

  AIMS: Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given the perceived involvement of mitochondrial dysfunction in HFpEF, this study was designed to examine the role of mitochondrial dynamics in the etiology of HFpEF.METHOD AND RESULTS: Adult mice were placed on a high fat diet plus l-NAME in drinking water ('two-hit' challenge to mimic obesity and hypertension) for 15 consecutive weeks. Mass spectrometry revealed pronounced changes in mitochondrial fission protein Drp1 and E3 ligase FBXL4 in 'two-hit' mouse hearts. Transfection of FBXL4 rescued against HFpEF-compromised diastolic function, cardiac geometry, and mitochondrial integrity without affecting systolic performance, in conjunction with altered mitochondrial dynamics and integrity (hyperactivation of Drp1 and unchecked fission). Mass spectrometry and co-IP analyses unveiled an interaction between FBXL4 and Drp1 to foster ubiquitination and degradation of Drp1. Truncated mutants of FBXL4 (Delta-Fbox) disengaged interaction between FBXL4 and Drp1. Metabolomic and proteomics findings identified deranged fatty acid and glucose metabolism in HFpEF patients and mice. A cellular model was established with concurrent exposure of high glucose and palmitic acid as a 'double-damage' insult to mimic diastolic anomalies in HFpEF. Transfection of FBXL4 mitigated 'double-damage'-induced cardiomyocyte diastolic dysfunction and mitochondrial injury, the effects were abolished and mimicked by Drp1 knock-in and knock-out, respectively. HFpEF downregulated sarco(endo)plasmic reticulum (SR) Ca2+ uptake protein SERCA2a while upregulating phospholamban, RYR1, IP3R1, IP3R3 and Na+-Ca2+ exchanger with unaltered SR Ca2+ load. FBXL4 ablated 'two-hit' or 'double-damage'-induced changes in SERCA2a, phospholamban and mitochondrial injury.
CONCLUSION: FBXL4 rescued against HFpEF-induced cardiac remodeling, diastolic dysfunction, and mitochondrial injury through reverting hyperactivation of Drp1-mediated mitochondrial fission, underscoring the therapeutic promises of FBXL4 in HFpEF.

Keywords:  Drp1; FBXL4; HFpEF; Intracellular Ca(2+); Mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.redox.2024.103081
Nat Commun. 2024 Feb 15. 15(1): 1391

Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.

Isabel Reinisch, Helene Michenthaler, Alba Sulaj, Elisabeth Moyschewitz, Jelena Krstic, Markus Galhuber, Ruonan Xu, Zina Riahi, Tongtong Wang, Nemanja Vujic, Melina Amor, Riccardo Zenezini Chiozzi, Martin Wabitsch, Dagmar Kolb, Anastasia Georgiadi, Lisa Glawitsch, Ellen Heitzer, Tim J Schulz, Michael Schupp, Wenfei Sun, Hua Dong, Adhideb Ghosh, Anne Hoffmann, Dagmar Kratky, Laura C Hinte, Ferdinand von Meyenn, Albert J R Heck, Matthias Blüher, Stephan Herzig, Christian Wolfrum, Andreas Prokesch.

In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.

DOI: https://doi.org/10.1038/s41467-024-45724-y
J Cachexia Sarcopenia Muscle. 2024 Feb 12.

Bed-rest and exercise remobilization: Concurrent adaptations in muscle glucose and protein metabolism.

Natalie F Shur, Elizabeth J Simpson, Hannah Crossland, Despina Constantin, Sally M Cordon, Dumitru Constantin-Teodosiu, Francis B Stephens, Matthew S Brook, Philip J Atherton, Kenneth Smith, Daniel J Wilkinson, Olivier E Mougin, Christopher Bradley, Ian A Macdonald, Paul L Greenhaff.

  BACKGROUND: Bed-rest (BR) of only a few days duration reduces muscle protein synthesis and induces skeletal muscle atrophy and insulin resistance, but the scale and juxtaposition of these events have not been investigated concurrently in the same individuals. Moreover, the impact of short-term exercise-supplemented remobilization (ESR) on muscle volume, protein turnover and leg glucose uptake (LGU) in humans is unknown.METHODS: Ten healthy males (24 ± 1 years, body mass index 22.7 ± 0.6 kg/m2 ) underwent 3 days of BR, followed immediately by 3 days of ESR consisting of 5 × 30 maximal voluntary single-leg isokinetic knee extensions at 90°/s each day. An isoenergetic diet was maintained throughout the study (30% fat, 15% protein and 55% carbohydrate). Resting LGU was calculated from arterialized-venous versus venous difference across the leg and leg blood flow during the steady-state of a 3-h hyperinsulinaemic-euglycaemic clamp (60 mU/m2 /min) measured before BR, after BR and after remobilization. Glycogen content was measured in vastus lateralis muscle biopsy samples obtained before and after each clamp. Leg muscle volume (LMV) was measured using magnetic resonance imaging before BR, after BR and after remobilization. Cumulative myofibrillar protein fractional synthetic rate (FSR) and whole-body muscle protein breakdown (MPB) were measured over the course of BR and remobilization using deuterium oxide and 3-methylhistidine stable isotope tracers that were administered orally.
RESULTS: Compared with before BR, there was a 45% decline in insulin-stimulated LGU (P < 0.05) after BR, which was paralleled by a reduction in insulin-stimulated leg blood flow (P < 0.01) and removal of insulin-stimulated muscle glycogen storage. These events were accompanied by a 43% reduction in myofibrillar protein FSR (P < 0.05) and a 2.5% decrease in LMV (P < 0.01) during BR, along with a 30% decline in whole-body MPB after 2 days of BR (P < 0.05). Myofibrillar protein FSR and LMV were restored by 3 days of ESR (P < 0.01 and P < 0.01, respectively) but not by ambulation alone. However, insulin-stimulated LGU and muscle glycogen storage were not restored by ESR.
CONCLUSIONS: Three days of BR caused concurrent reductions in LMV, myofibrillar protein FSR, myofibrillar protein breakdown and insulin-stimulated LGU, leg blood flow and muscle glycogen storage in healthy, young volunteers. Resistance ESR restored LMV and myofibrillar protein FSR, but LGU and muscle glycogen storage remained depressed, highlighting divergences in muscle fuel and protein metabolism. Furthermore, ambulation alone did not restore LMV and myofibrillar protein FSR in the non-exercised contralateral limb, emphasizing the importance of exercise rehabilitation following even short-term BR.

Keywords:  human metabolism; immobilization; insulin sensitivity; leg glucose uptake; muscle atrophy; muscle gene expression; muscle glycogen storage; muscle protein breakdown; muscle protein synthesis; rehabilitation

DOI:  https://doi.org/10.1002/jcsm.13431