bims-kimdis 2024-06-23 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–06–23
seventeen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Characterization of β-Hydroxybutyrate as a Cell Autonomous Fuel for Active Excitatory and Inhibitory Neurons.
Possible role of β-hydroxybutyrate in inducing inflammation in alopecia areata.
Beta-Hydroxybutyrate Mitigates Sensorimotor and Cognitive Impairments in a Photothrombosis-Induced Ischemic Stroke in Mice.
Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.
Mitochondria Transplantation: Rescuing Innate Muscle Bioenergetic Impairment in a Model of Aging and Exercise Intolerance.
Intramuscular diacylglycerol accumulates with acute hyperinsulinemia in insulin-resistant phenotypes.
Skeletal muscle as a pro- and anti-inflammatory tissue: insights from children to adults and ultrasound findings.
Skeletal muscle immobilisation-induced atrophy: mechanistic insights from human studies.
Is mitochondrial morphology important for cellular physiology?
The effects of high-intensity interval training versus moderate-intensity continuous training on athletes' aerobic endurance performance parameters.
Mitochondria and cell death.
Euglycemic Ketoacidosis and Lactic Acidosis Associated With Metformin Toxicity.
Novel NLRP3 inhibitor INF195: Low doses provide effective protection against myocardial ischemia/reperfusion injury.
The role of the kynurenine pathway in cardiovascular disease.
Sex Differences in Energy Metabolism: A Female-Oriented Discussion.
The Contractile Machines of the Heart.
Impact of low-load resistance exercise with and without blood flow restriction on muscle strength, endurance, and oxidative capacity: A pilot study.

bioRxiv. 2024 Jun 09. pii: 2024.06.08.598077. [Epub ahead of print]

Characterization of β-Hydroxybutyrate as a Cell Autonomous Fuel for Active Excitatory and Inhibitory Neurons.

Kirsten Bredvik, Charmaine Liu, Timothy A Ryan.

The ketogenic diet is an effective treatment for drug-resistant epilepsy, but the therapeutic mechanisms are poorly understood. Although ketones are able to fuel the brain, it is not known whether ketones are directly metabolized by neurons on a time scale sufficiently rapid to fuel the bioenergetic demands of sustained synaptic transmission. Here, we show that nerve terminals can use the ketone β-hydroxybutyrate in a cell- autonomous fashion to support neurotransmission in both excitatory and inhibitory nerve terminals and that this flexibility relies on Ca 2+ dependent upregulation of mitochondrial metabolism. Using a genetically encoded ATP sensor, we show that inhibitory axons fueled by ketones sustain much higher ATP levels under steady state conditions than excitatory axons, but that the kinetics of ATP production following activity are slower when using ketones as fuel compared to lactate/pyruvate for both excitatory and inhibitory neurons.
Significance Statement: The ketogenic diet is a standard treatment for drug resistant epilepsy, but the mechanism of treatment efficacy is largely unknown. Changes to excitatory and inhibitory balance is one hypothesized mechanism. Here, we determine that ATP levels are differentially higher in inhibitory neurons compared to excitatory neurons, suggesting that greater mitochondrial ATP production in inhibitory neurons could be one mechanism mediating therapeutic benefit. Further, our studies of ketone metabolism by synaptic mitochondria should inform management of side effects and risks associated with ketogenic diet treatments. These results provide novel insights that clarify the role of ketones at the cellular level in ketogenic diet treatment for intractable epilepsy and inform the use of ketogenic diets for neurologic and psychiatric conditions more broadly.

DOI: https://doi.org/10.1101/2024.06.08.598077
Exp Dermatol. 2024 Jun;33(6): e15117

Possible role of β-hydroxybutyrate in inducing inflammation in alopecia areata.

Jung-Min Shin, Seungjin Son, Kyung Eun Jung, Chang Deok Kim, Young Lee.

  Alopecia areata (AA) is an autoimmune inflammatory disease characterized by non-scarring hair loss due to an immune response that targets hair follicles. The current treatment approach for AA involves the use of immunosuppressants and immunomodulators to reduce cytokine levels around affected hair follicles. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as potential anti-inflammatory agents with diverse beneficial effects in various medical conditions. This study investigates the role of beta-hydroxybutyrate (BHB), a ketone body produced during SGLT2 inhibition, in the pathogenesis of AA. Serum BHB levels were found to be significantly elevated in patients with AA compared with healthy controls, with higher levels correlating with severity of hair loss. BHB treatment increased inflammatory cytokine production in outer root sheath (ORS) cells, mimicking the inflammatory conditions seen in AA. The results suggest that elevated BHB levels may exacerbate the inflammatory immune response in AA patients and may be associated with chronic hair loss and resistance to treatment. Serum BHB levels may serve as a potential marker of poor prognosis in patients with severe AA. Further research is needed to elucidate the precise role of BHB in the pathogenesis of AA and its implications for disease management.

Keywords:  alopecia areata; inflammation; β‐hydroxybutyrate

DOI:  https://doi.org/10.1111/exd.15117
Int J Mol Sci. 2024 May 24. pii: 5710. [Epub ahead of print]25(11):

Beta-Hydroxybutyrate Mitigates Sensorimotor and Cognitive Impairments in a Photothrombosis-Induced Ischemic Stroke in Mice.

Artem P Gureev, Irina S Sadovnikova, Ekaterina V Chernyshova, Arina D Tsvetkova, Polina I Babenkova, Veronika V Nesterova, Ekaterina P Krutskikh, Daria E Volodina, Natalia A Samoylova, Nadezda V Andrianova, Denis N Silachev, Egor Y Plotnikov.

  The consequences of stroke include cognitive deficits and sensorimotor disturbances, which are largely related to mitochondrial impairments in the brain. In this work, we have shown that the mimetic of the ketogenic diet beta-hydroxybutyrate (βHB) can improve neurological brain function in stroke. At 3 weeks after photothrombotic stroke, mice receiving βHB with drinking water before and after surgery recovered faster in terms of sensorimotor functions assessed by the string test and static rods and cognitive functions assessed by the Morris water maze. At the same time, the βHB-treated mice had lower expression of some markers of astrocyte activation and inflammation (Gfap, Il-1b, Tnf). We hypothesize that long-term administration of βHB promotes the activation of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway, which leads to increased expression of antioxidant genes targeting mitochondria and genes involved in signaling pathways necessary for the maintenance of synaptic plasticity. βHB partially maintained mitochondrial DNA (mtDNA) integrity during the first days after photothrombosis. However, in the following three weeks, the number of mtDNA damages increased in all experimental groups, which coincided with a decrease in Ogg1 expression, which plays an important role in mtDNA repair. Thus, we can assume that βHB is not only an important metabolite that provides additional energy to brain tissue during recovery from stroke under conditions of mitochondrial damage but also an important signaling molecule that supports neuronal plasticity and reduces neuroinflammation.

Keywords:  ischemia; mitochondria; neuroprotection; oxidative stress; stroke

DOI:  https://doi.org/10.3390/ijms25115710
bioRxiv. 2024 Jun 09. pii: 2024.06.06.597841. [Epub ahead of print]

Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.

Rachel C Weiss, Kelly D Pyles, Kevin Cho, Michelle Brennan, Jonathan S Fisher, Gary J Patti, Kyle S McCommis.

Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown.
Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of U- 13 C-glucose. Cardiac glycogen was assessed biochemically and by transmission electron microscopy. Cardiac uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the CS-Mpc2-/- heart failure. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed low-fat or ketogenic diet.
Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, yet these hearts displayed increased enrichment from U- 13 C-glucose and increased glycolytic metabolite pool sizes. 13 C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ∼6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13 C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin-II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet.
Conclusions: Our results indicate that loss of MPC in the heart causes glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is reduced by consumption of a ketogenic diet.

DOI: https://doi.org/10.1101/2024.06.06.597841
J Strength Cond Res. 2024 Jul 01. 38(7): 1189-1199

Mitochondria Transplantation: Rescuing Innate Muscle Bioenergetic Impairment in a Model of Aging and Exercise Intolerance.

Tasnim Arroum, Gerald A Hish, Kyle J Burghardt, Mohamed Ghamloush, Belal Bazzi, Abdallah Mrech, Paul T Morse, Steven L Britton, Lauren G Koch, James D McCully, Maik Hüttemann, Moh H Malek.

ABSTRACT: Arroum, T, Hish, GA, Burghardt, KJ, Ghamloush, M, Bazzi, B, Mrech, A, Morse, PT, Britton, SL, Koch, LG, McCully, JD, Hüttemann, M, and Malek, MH. Mitochondria transplantation: Rescuing innate muscle bioenergetic impairment in a model of aging and exercise intolerance. J Strength Cond Res 38(7): 1189-1199, 2024-Mitochondria, through oxidative phosphorylation, are crucial for energy production. Disease, genetic impairment, or deconditioning can harm muscle mitochondria, affecting energy production. Endurance training enhances mitochondrial function but assumes mobility. Individuals with limited mobility lack effective treatments for mitochondrial dysfunction because of disease or aging. Mitochondrial transplantation replaces native mitochondria that have been damaged with viable, respiration-competent mitochondria. Here, we used a rodent model selectively bred for low-capacity running (LCR), which exhibits innate mitochondrial dysfunction in the hind limb muscles. Hence, the purpose of this study was to use a distinct breed of rats (i.e., LCR) that display hereditary skeletal muscle mitochondrial dysfunction to evaluate the consequences of mitochondrial transplantation. We hypothesized that the transplantation of mitochondria would effectively alleviate mitochondrial dysfunction in the hind limb muscles of rats when compared with placebo injections. In addition, we hypothesized that rats receiving the mitochondrial transplantation would experience an improvement in their functional capacity, as evaluated through incremental treadmill testing. Twelve aged LCR male rats (18 months old) were randomized into 2 groups (placebo or mitochondrial transplantation). One LCR rat of the same age and sex was used as the donor to isolate mitochondria from the hindlimb muscles. Isolated mitochondria were injected into both hindlimb muscles (quadriceps femoris, tibialis anterior (TA), and gastrocnemius complex) of a subset LCR (n = 6; LCR-M) rats. The remaining LCR (n = 5; LCR-P) subset received a placebo injection containing only the vehicle without the isolated mitochondria. Four weeks after mitochondrial transplantation, rodents were euthanized and hindlimb muscles harvested. The results indicated a significant (p < 0.05) increase in mitochondrial markers for glycolytic (plantaris and TA) and mixed (quadricep femoris) muscles, but not oxidative muscle (soleus). Moreover, we found significant (p < 0.05) epigenetic changes (i.e., hypomethylation) at the global and site-specific levels for a key mitochondrial regulator (transcription factor A mitochondrial) between the placebo and mitochondrial transplantation groups. To our knowledge, this is the first study to examine the efficacy of mitochondrial transplantation in a rodent model of aging with congenital skeletal muscle dysfunction.

DOI: https://doi.org/10.1519/JSC.0000000000004793
Am J Physiol Endocrinol Metab. 2024 Jun 19.

Intramuscular diacylglycerol accumulates with acute hyperinsulinemia in insulin-resistant phenotypes.

Colleen F McKenna, Harrison D Stierwalt, Karin A Zemski Berry, Sarah E Ehrlicher, Matthew M Robinson, Simona Zarini, Darcy E Kahn, Janet K Snell-Bergeon, Leigh Perreault, Bryan C Bergman, Sean A Newsom.

  Elevated skeletal muscle diacylglycerols (DAG) and ceramides can impair insulin signaling, and acylcarnitines (acylCN) reflect impaired fatty acid oxidation, thus the intramuscular lipid profile is indicative of insulin resistance. Acute (i.e., postprandial) hyperinsulinemia has been shown to elevate lipids in healthy muscle and is an independent risk factor for type 2 diabetes (T2D). It is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts, thus contributing to or exacerbating insulin resistance. We investigated the impact of acute hyperinsulinemia on the muscle lipidome in order to help characterize the physiological basis in which hyperinsulinemia elevates T2D risk. Endurance athletes (n=12), sedentary lean adults (n=12), and individuals with obesity (n=13) and T2D (n=7) underwent a hyperinsulinemic-euglycemic clamp with muscle biopsies. While there were no significant differences in total 1,2-DAG fluctuations, there was a 2% decrease in athletes versus a 53% increase in T2D. C18 1,2-DAGs increased during the clamp with T2D only, which negatively correlated with insulin sensitivity. Basal muscle C18:0 ceramides were elevated with T2D, but not altered by clamp. Acylcarnitines were universally lowered during hyperinsulinemia, with more robust reductions of 80% in athletes compared to only 46% with T2D. Similar fluctuations with acute hyperinsulinemia increasing 1,2 DAGs in insulin-resistant phenotypes and universally lowering acylcarnitines were observed in male mice. In conclusion, acute hyperinsulinemia elevates muscle 1,2-DAG levels with insulin-resistant phenotypes. This suggests a possible dysregulation of intramuscular lipid metabolism in the fed state in individuals with low insulin sensitivity, which may exacerbate insulin resistance.

Keywords:  acylcarnitine; ceramides; diacylglycerol; insulin resistance; skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00368.2023
J Ultrasound. 2024 Jun 21.

Skeletal muscle as a pro- and anti-inflammatory tissue: insights from children to adults and ultrasound findings.

Armando Di Ludovico, Saverio La Bella, Francesca Ciarelli, Francesco Chiarelli, Luciana Breda, Angelika Mohn.

  Previously regarded as a movement and posture control agent, the skeletal muscle is now recognized as an endocrine organ that may affect systemic inflammation and metabolic health. The discovery of myokines such as IL-6, released from skeletal muscle in response to physical exercise, is now one of the most recent insights. Myokines are the mediators of the balance between the pro-inflammatory and anti-inflammatory responses. This underscores the muscle function as a determinant of good health and prevention of diseases. Advances in ultrasound technology improved evaluation of muscle thickness, composition, and determining fat distribution. Combining imaging with molecular biology, researchers discovered the complicated interplay between muscle function, cytokine production and general health effects.The production of myokines with exercise showcasing the adaptability of muscles to high-stress conditions and contributing to metabolism and inflammation regulation. These findings have significant implications in order to provide improvement in metabolic and inflammatory diseases.

Keywords:  Adipokines; Inflammation; Myokines; Obesity; Ultrasound

DOI:  https://doi.org/10.1007/s40477-024-00917-5
Clin Sci (Lond). 2024 Jun 19. 138(12): 741-756

Skeletal muscle immobilisation-induced atrophy: mechanistic insights from human studies.

Colleen S Deane, Matthew Piasecki, Philip J Atherton.

  Periods of skeletal muscle disuse lead to rapid declines in muscle mass (atrophy), which is fundamentally underpinned by an imbalance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). The complex interplay of molecular mechanisms contributing to the altered regulation of muscle protein balance during disuse have been investigated but rarely synthesised in the context of humans. This narrative review discusses human models of muscle disuse and the ensuing inversely exponential rate of muscle atrophy. The molecular processes contributing to altered protein balance are explored, with a particular focus on growth and breakdown signalling pathways, mitochondrial adaptations and neuromuscular dysfunction. Finally, key research gaps within the disuse atrophy literature are highlighted providing future avenues to enhance our mechanistic understanding of human disuse atrophy.

Keywords:  atrophy; disuse; skeletal muscle

DOI:  https://doi.org/10.1042/CS20231198
Trends Endocrinol Metab. 2024 Jun 11. pii: S1043-2760(24)00123-1. [Epub ahead of print]

Is mitochondrial morphology important for cellular physiology?

Timothy Wai.

  Mitochondria are double membrane-bound organelles the network morphology of which in cells is shaped by opposing events of fusion and fission executed by dynamin-like GTPases. Mutations in these genes can perturb the form and functions of mitochondria in cell and animal models of mitochondrial diseases. An expanding array of chemical, mechanical, and genetic stressors can converge on mitochondrial-shaping proteins and disrupt mitochondrial morphology. In recent years, studies aimed at disentangling the multiple roles of mitochondrial-shaping proteins beyond fission or fusion have provided insights into the homeostatic relevance of mitochondrial morphology. Here, I review the pleiotropy of mitochondrial fusion and fission proteins with the aim of understanding whether mitochondrial morphology is important for cell and tissue physiology.

Keywords:  fission and fusion; genetic disease; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology

DOI:  https://doi.org/10.1016/j.tem.2024.05.005
Eur J Appl Physiol. 2024 Jun 21.

The effects of high-intensity interval training versus moderate-intensity continuous training on athletes' aerobic endurance performance parameters.

Ziyi Wang, Jun Wang.

   OBJECTIVE: To systematically evaluate and meta-analyze the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on athletes of aerobic endurance performance parameters.
METHODS: PubMed, Web of Science, EBSCO, Embase, and Cochrane databases were searched. The assessment of quality was conducted employing The Cochrane Risk of Bias Assessment Tool, while heterogeneity examination and subgroup analysis were performed. Moreover, regression and sensitivity analyses were executed.
RESULTS: There was no significant difference between the effects of HIIT and MICT on the enhancement of athletes' running economy (RE) (P > 0.05); 1-3 weeks and 4-9 weeks of HIIT were more effective in improving athletes' maximum oxygen uptake (VO2max) (P < 0.05), and 10 weeks and above were not significant (P > 0.05); 1-3 weeks of HIIT was more effective in improving athletes' anaerobic threshold (AT) (P < 0.05), and 4-10 weeks was not significant (P > 0.05); 3 weeks of high-intensity interval training (HIIT) did not significantly enhance athletes' minute ventilation (VE) (P > 0.05), whereas a duration of 6-10 weeks yielded superior results (P < 0.05); 8 weeks of moderate-intensity continuous training (MICT) did not significantly enhance athletes' hemoglobin (Hb) level (P > 0.05), whereas a duration of 2-3 weeks yielded superior results (P < 0.05).
CONCLUSIONS: (1) HIIT and MICT have similar effects on enhancing athletes' RE. (2) 6-9 weeks' HIIT was more effective in improving athletes' VO2max and VE, and 3 weeks' HIIT was more effective in improving athletes' AT. (3) Within 3 weeks, MICT was more effective in improving the Hb level of athletes.
REGISTRATION NUMBER ON PROSPERO: CRD42024499039.

Keywords:  Aerobic capacity; Athletes; Exercise performance; High-intensity interval training; Moderate-intensity continuous training

DOI:  https://doi.org/10.1007/s00421-024-05532-0
Nat Cell Biol. 2024 Jun 20.

Mitochondria and cell death.

Hannah L Glover, Annabell Schreiner, Grant Dewson, Stephen W G Tait.

Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.

DOI: https://doi.org/10.1038/s41556-024-01429-4
Cureus. 2024 May;16(5): e60661

Euglycemic Ketoacidosis and Lactic Acidosis Associated With Metformin Toxicity.

Feras Al-Moussally, Jung-Jung Tien, Kanya Rajagopalan, Carlos Boterosuarez, Roger Crouse.

  In patients with diabetes, diabetic ketoacidosis (DKA) is a well-documented potential complication, usually presenting with hyperglycemia, anion gap acidosis, and positive ketones. Metformin toxicity in the setting of acute renal failure is also a well-known cause of lactic acidosis. However, metformin-induced euglycemic ketoacidosis is less well-known or studied. We report a case of metformin toxicity in the setting of acute renal failure with both lactic acidosis and ketosis and an initial confounded clinical presentation of sulphonylurea-induced hypoglycemia. A high index of suspicion for metformin-associated lactic acidosis (MALA) and metformin-associated lactic acidosis with euglycemic ketoacidosis (MALKA) should be in place in patients who are taking metformin and presenting with acute renal failure and euglycemia.

Keywords:  diabetes; diabetes type 2; euglycemia; hypoglycemia; mellitus; metformin

DOI:  https://doi.org/10.7759/cureus.60661
Vascul Pharmacol. 2024 Jun 17. pii: S1537-1891(24)00123-X. [Epub ahead of print] 107397

Novel NLRP3 inhibitor INF195: Low doses provide effective protection against myocardial ischemia/reperfusion injury.

Simone Gastaldi, Magalì Giordano, Federica Blua, Chiara Rubeo, Valentina Boscaro, Saveria Femminò, Stefano Comità, Eleonora Gianquinto, Vanessa Landolfi, Elisabetta Marini, Margherita Gallicchio, Francesca Spyrakis, Pasquale Pagliaro, Massimo Bertinaria, Claudia Penna.

   BACKGROUND: Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and caspase-1. However, NLRP3 may paradoxically exhibit cardioprotective properties. This study aimed to assess the protective effects of the novel NLRP3 inhibitor, INF195, both in vitro and ex vivo.
METHODS: To investigate the relationship between NLRP3 and myocardial IRI, we synthetized a series of novel NLRP3 inhibitors, and investigated their putative binding mode via docking studies. Through in vitro studies we identified INF195 as optimal for NLRP3 inhibition. We measured infarct-size in isolated mouse hearts subjected to 30-min global ischemia/one-hour reperfusion in the presence of three different doses of INF195 (5, 10, or 20-μM). We analyzed caspase-1 and IL-1β concentration in cardiac tissue homogenates by ELISA. Statistical significance was determined using one-way ANOVA followed by Tukey's test.
RESULTS AND CONCLUSION: INF195 reduces NLRP3-induced pyroptosis in human macrophages. Heart pre-treatment with 5 and 10-μM INF195 significantly reduces both infarct size and IL-1β levels. Data suggest that intracardiac NLRP3 activation contributes to IRI and that low doses of INF195 exert cardioprotective effects by reducing infarct size. However, at 20-μM, INF195 efficacy declines, leading to a lack of cardioprotection. Research is required to determine if high doses of INF195 have off-target effects or dual roles, potentially eliminating both harmful and cardioprotective functions of NLRP3. Our findings highlight the potential of a new chemical scaffold, amenable to further optimization, to provide NLRP3 inhibition and cardioprotection in the ischemia/reperfusion setting.

Keywords:  Cardioprotection; Interleukin-1β; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.vph.2024.107397
Front Cardiovasc Med. 2024 ;11 1406856

The role of the kynurenine pathway in cardiovascular disease.

Yuehang Yang, Xing Liu, Xinyi Liu, Chiyang Xie, Jiawei Shi.

  The kynurenine pathway (KP) serves as the primary route for tryptophan metabolism in most mammalian organisms, with its downstream metabolites actively involved in various physiological and pathological processes. Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) serve as the initial and pivotal enzymes of the KP, with IDO playing important and intricate roles in cardiovascular diseases. Multiple metabolites of KP have been observed to exhibit elevated concentrations in plasma across various cardiovascular diseases, such as atherosclerosis, hypertension, and acute myocardial infarction. Multiple studies have indicated that kynurenine (KYN) may serve as a potential biomarker for several adverse cardiovascular events. Furthermore, Kynurenine and its downstream metabolites have complex roles in inflammation, exhibiting both inhibitory and stimulatory effects on inflammatory responses under different conditions. In atherosclerosis, upregulation of IDO stimulates KYN production, mediating aromatic hydrocarbon receptor (AhR)-induced exacerbation of vascular inflammation and promotion of foam cell formation. Conversely, in arterial calcification, this mediation alleviates osteogenic differentiation of vascular smooth muscle cells. Additionally, in cardiac remodeling, KYN-mediated AhR activation exacerbates pathological left ventricular hypertrophy and fibrosis. Interventions targeting components of the KP, such as IDO inhibitors, 3-hydroxyanthranilic acid, and anthranilic acid, demonstrate cardiovascular protective effects. This review outlines the mechanistic roles of KP in coronary atherosclerosis, arterial calcification, and myocardial diseases, highlighting the potential diagnostic, prognostic, and therapeutic value of KP in cardiovascular diseases, thus providing novel insights for the development and application of related drugs in future research.

Keywords:  arterial calcification; cardiovascular diseases; coronary atherosclerosis; kynurenine pathway; myocardial diseases

DOI:  https://doi.org/10.3389/fcvm.2024.1406856
Sports Med. 2024 Jun 18.

Sex Differences in Energy Metabolism: A Female-Oriented Discussion.

Barbara N Sanchez, Jeff S Volek, William J Kraemer, Catherine Saenz, Carl M Maresh.

The purpose of this review is to delineate aspects of energy metabolism at rest and during exercise that may be subject to sex differences and the potential underlying mechanisms involved. It focuses on distinct aspects of female physiology with an oriented discussion following the reproductive life stages of healthy, eumenorrheic females, including premenopausal time frames, pregnancy, perimenopause, and menopause. Finally, this review aims to address methodological challenges surrounding sexual dimorphism in energy metabolism investigations and confounding factors in this field. During resting conditions, females tend to have higher rates of non-oxidative free fatty acid clearance, which could contribute to lower respiratory exchange ratio measures. At the same time, carbohydrate energy metabolism findings are mixed. In general, females favor lipid energy metabolism during moderate-intensity exercise, while men favor carbohydrate energy metabolism. Factors such as age, dietary intake, genetics, and methodological decisions confound study findings, including properly identifying and reporting the menstrual cycle phase when female subjects are eumenorrheic. Pregnancy presents a unique shift in physiological systems, including energy metabolism, which can be observed at rest and during exercise. Changes in body composition and hormonal levels during the post-menopausal period directly impact energy metabolism, specifically lipid metabolism. This change in physiological state factors into the evidence showing a reduction in our understanding of sex differences in lipid metabolism during exercise in older adults. This review reveals a need for a focused understanding of female energy metabolism that could help exercise and nutrition professionals optimize female health and performance across the lifespan.

DOI: https://doi.org/10.1007/s40279-024-02063-8
Adv Exp Med Biol. 2024 ;1441 417-433

The Contractile Machines of the Heart.

Ingo Morano.

  This chapter will describe basic structural and functional features of the contractile apparatus of muscle cells of the heart, namely, cardiomyocytes and smooth muscle cells. Cardiomyocytes form the contractile myocardium of the heart, while smooth muscle cells form the contractile coronary vessels. Both muscle types have distinct properties and will be considered with respect to their cellular appearance (brick-like cross-striated versus spindle-like smooth), arrangement of contractile proteins (sarcomeric versus non-sarcomeric organization), calcium activation mechanisms (thin-filament versus thick-filament regulation), contractile features (fast and phasic versus slow and tonic), energy metabolism (high oxygen versus low oxygen demand), molecular motors (type II myosin isoenzymes with high adenosine diphosphate [ADP]-release rate versus myosin isoenzymes with low ADP-release rates), chemomechanical energy conversion (high adenosine triphosphate [ATP] consumption and short duty ratio versus low ATP consumption and high duty ratio of myosin II cross-bridges [XBs]), and excitation-contraction coupling (calcium-induced calcium release versus pharmacomechanical coupling). Part of the work has been published (Neuroscience - From Molecules to Behavior", Chap. 22, Galizia and Lledo eds 2013, Springer-Verlag; with kind permission from Springer Science + Business Media).

Keywords:  ADP; ATP; Actin; Adenylate cyclase; Calcium; Calcium channel; Calsequestrin; Cardiomyocytes; Cell-cell junctions; Chronotropy; Contractile proteins; Coronary vessels; Cross-striation; Diastole; Endocardium; Epicardium; Excitation-contraction coupling; Frank-Starling mechanism; Gap junctions; Heartbeat; IP3 receptor; IP3R; Inotropy; Isometric contraction; Isotonic contraction; MYH; Muscle; Myocardium; Myofibrils; Myosin; Myosin heavy chain; Myosin-binding protein C; Oxygen; Oxygen consumption; PKA; Phosphorylation; Ryanodine receptor; SERCA; Sarcomere; Sarcoplasmic reticulum; Smooth muscle cells; Systole; Thick filament; Thin filament; Titin; Tropomyosin; Troponin

DOI:  https://doi.org/10.1007/978-3-031-44087-8_21
Physiol Rep. 2024 Jun;12(12): e16041

Impact of low-load resistance exercise with and without blood flow restriction on muscle strength, endurance, and oxidative capacity: A pilot study.

Brett H Davis, James E Stampley, Joshua Granger, Matthew C Scott, Timothy D Allerton, Neil M Johannsen, Guillaume Spielmann, Brian A Irving.

  Low-load resistance exercise (LLRE) to failure can increase muscle mass, strength, endurance, and mitochondrial oxidative capacity (OXPHOS). However, the impact of adding blood flow restriction to low-load resistance exercise (LLBFR) when matched for volume on these outcomes is incompletely understood. This pilot study examined the impact of 6 weeks of single-legged LLBFR and volume-matched LLRE on thigh bone-free lean mass, strength, endurance, and mitochondrial OXPHOS. Twenty (12 males and 8 females) untrained young adults (mean ± SD; 21 ± 2 years, 168 ± 11 cm, 68 ± 12 kg) completed 6 weeks of either single-legged LLBFR or volume-matched LLRE. Participants performed four sets of 30, 15, 15, and 15 repetitions at 25% 1-RM of leg press and knee extension with or without BFR three times per week. LLBFR increased knee extension 1-RM, knee extension endurance, and thigh bone-free lean mass relative to control (all p < 0.05). LLRE increased leg press and knee extension 1-RM relative to control (p = 0.012 and p = 0.054, respectively). LLRE also increased mitochondrial OXPHOS (p = 0.047 (nonparametric)). Our study showed that LLBFR increased muscle strength, muscle endurance, and thigh bone-free lean mass in the absence of improvements in mitochondrial OXPHOS. LLRE improved muscle strength and mitochondrial OXPHOS in the absence of improvements in thigh bone-free lean mass or muscle endurance.

Keywords:  NIRS; exercise; human; near‐infrared spectroscopy; training

DOI:  https://doi.org/10.14814/phy2.16041