bims-kimdis 2024-05-05 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒05‒05
fourteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischemic heart failure.
A very-low-calorie ketogenic diet normalises obesity-related enhanced levels of erythropoietin compared with a low-calorie diet or bariatric surgery.
Acute effects of a ketone monoester, whey protein, or their co-ingestion on mTOR trafficking and protein-protein co-localization in human skeletal muscle.
The ketone body β-Hydroxybutyrate as a fuel source of chondrosarcoma cells.
A randomized open-label, observational study of the novel ketone ester, bis octanoyl (R)-1,3-butanediol, and its acute effect on ß-hydroxybutyrate and glucose concentrations in healthy older adults.
MCU genetically altered mice suggest how mitochondrial Ca2+ regulates metabolism.
Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial.
NLRP3 inflammasome and pyroptosis in cardiovascular diseases and exercise intervention.
Not Only Protein: Dietary Supplements to Optimize the Skeletal Muscle Growth Response to Resistance Training: The Current State of Knowledge.
Obesity-induced skeletal muscle remodeling: A comparative analysis of exercise training and ACE-inhibitory drug in male mice.
Short-Chain Fatty Acid Butyrate Is an Inotropic Agent With Vasorelaxant and Cardioprotective Properties.
Mitochondrial dynamics: updates and perspectives.
Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches.
Brain-muscle communication prevents muscle aging by maintaining daily physiology.

Cardiovasc Res. 2024 May 01. pii: cvae092. [Epub ahead of print]

The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischemic heart failure.

Kim L Ho, Qutuba Karwi, Faqi Wang, Cory Wagg, Liyan Zhang, Sai Panidarapu, Brandon Chen, Simran Pherwani, Amanda A Greenwell, Gavin Oudit, John R Ussher, Gary D Lopaschuk.

AIMS: Cardiac energy metabolism is perturbed in ischemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure.METHODS: C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending (LAD) coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and ß-hydroxybutyrate (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis.
RESULTS: Mice with heart failure exhibited a 56% drop in ejection fraction which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet no increase in overall cardiac energy production was observed, and instead there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet.
CONCLUSIONS: We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischemic heart and a decrease in insulin-stimulated glucose oxidation.

DOI: https://doi.org/10.1093/cvr/cvae092
J Endocrinol Invest. 2024 May 02.

A very-low-calorie ketogenic diet normalises obesity-related enhanced levels of erythropoietin compared with a low-calorie diet or bariatric surgery.

A Fernandez-Pombo, P M Lorenzo, M C Carreira, D Gomez-Arbelaez, A I Castro, D Primo, J Rodriguez, I Sajoux, J Baltar, D de Luis, D Bellido, A B Crujeiras, F F Casanueva.

  PURPOSE: Nutritional ketosis synergistically with body-weight loss induced by a very-low-calorie ketogenic diet (VLCKD) has proven to be effective in improving obesity-related pathophysiology. Recently, growing attention has been focused on the relation between erythropoietin (EPO) and obesity. Thus, this study aims to investigate whether nutritional ketosis and weight loss induced by a VLCKD modify the circulating levels of EPO in patients with obesity in comparison with the effect of low-calorie diet (LCD) or bariatric surgery (BS).METHODS: EPO levels, iron status and body composition parameters were evaluated in 72 patients with overweight or obesity and 27 normal-weight subjects at baseline and after the three different weight-reduction therapies (VLCKD, LCD and BS) in 69 patients with excess body weight. β-hydroxybutyrate levels were also measured in the VLCKD group. The follow-up was established at 2-3 months and 4-6 months.
RESULTS: It was found that EPO levels were higher in morbid obesity and correlated with higher basal weight, fat mass (FM) and fat-free mass (FFM) in the overall sample. High baseline EPO levels were also correlated with higher impact on the course of weight loss and changes in FM and FFM induced by the three weight-loss interventions. Furthermore, the VLCKD induced a decrease in EPO levels coinciding with maximum ketosis, which was maintained over time, while statistically significant changes were not observed after LCD and BS.
CONCLUSION: The obesity-related increased EPO levels are restored after VLCKD intervention at the time of maximum ketosis, suggesting a potential role of the nutritional ketosis induced by the VLCKD. Baseline EPO levels could be a biomarker of response to a weight-loss therapy.

Keywords:  Adiposity; Energy restriction; Erythropoietin; Ketone bodies; Nutritional ketosis

DOI:  https://doi.org/10.1007/s40618-024-02364-9
Am J Physiol Cell Physiol. 2024 Apr 29.

Acute effects of a ketone monoester, whey protein, or their co-ingestion on mTOR trafficking and protein-protein co-localization in human skeletal muscle.

Sarkis J Hannaian, Jamie Lov, Zacharie Cheng-Boivin, Sidney Abou Sawan, Nathan Hodson, Benoit J Gentil, José A Morais, Tyler A Churchward-Venne.

  We recently demonstrated that acute oral ketone monoester intake induces a stimulation of postprandial myofibrillar protein synthesis rates comparable to that elicited following the ingestion of 10 g whey protein or their co-ingestion. The present investigation aimed to determine the acute effects of ingesting a ketone monoester, whey protein, or their co-ingestion on mTOR-related protein-protein co-localization and intracellular trafficking in human skeletal muscle. In a randomized, double-blind, parallel group design, 36 healthy recreationally active young males (age: 24.2±4.1 y) ingested either: 1) 0.36 g ∙ kg-1 bodyweight of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET+PRO). Muscle biopsies were obtained in the overnight postabsorptive state (basal conditions), and at 120- and 300-minutes in the postprandial period for immunofluorescence assessment of protein translocation and co-localization of mTOR-related signaling molecules. All treatments resulted in a significant (Interaction: P<0.0001) decrease in tuberous sclerosis complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) co-localization at 120-minutes vs. basal; however, the decrease was sustained at 300-minutes vs. basal (P<0.0001) only in KET+PRO. PRO and KET+PRO increased (Interaction: P<0.0001) mTOR-Rheb co-localization at 120-minutes vs. basal; however, KET+PRO resulted in a sustained increase in mTOR-Rheb co-localization at 300-minutes that was greater than KET and PRO. Treatment intake increased mTOR-wheat germ agglutinin (WGA) co-localization at 120- and 300-minutes (Time: P=0.0031), suggesting translocation toward the fiber periphery. These findings demonstrate that ketone monoester intake can influence the spatial mechanisms involved in the regulation of mTORC1 in human skeletal muscle.

Keywords:  Rheb; TSC2; beta-hydroxybutyrate; immunofluorescence; ketone bodies

DOI:  https://doi.org/10.1152/ajpcell.00207.2024
Heliyon. 2024 May 15. 10(9): e30212

The ketone body β-Hydroxybutyrate as a fuel source of chondrosarcoma cells.

Misael Vargas-López, Carlos A Quiroz-Vicente, Nury Pérez-Hernández, Fernando Gómez-Chávez, Angel E Bañuelos-Hernández, Elizabeth Pérez-Hernández.

  Chondrosarcoma (CS) is a malignant bone tumor arising from cartilage-producing cells. The conventional subtype of CS typically develops within a dense cartilaginous matrix, creating an environment deficient in oxygen and nutrients, necessitating metabolic adaptation to ensure proliferation under stress conditions. Although ketone bodies (KBs) are oxidized by extrahepatic tissue cells such as the heart and brain, specific cancer cells, including CS cells, can undergo ketolysis. In this study, we found that KBs catabolism is activated in CS cells under nutrition-deprivation conditions. Interestingly, cytosolic β-hydroxybutyrate dehydrogenase 2 (BDH2), rather than mitochondrial BDH1, is expressed in these cells, indicating a specific metabolic adaptation for ketolysis in this bone tumor. The addition of the KB, β-Hydroxybutyrate (β-HB) in serum-starved CS cells re-induced the expression of BDH2, along with the key ketolytic enzyme 3-oxoacid CoA-transferase 1 (OXCT1) and monocarboxylate transporter-1 (MCT1). Additionally, internal β-HB production was quantified in supplied and starved cells, suggesting that CS cells are also capable of ketogenesis alongside ketolysis. These findings unveil a novel metabolic adaptation wherein nutrition-deprived CS cells utilize KBs for energy supply and proliferation.

Keywords:  Chondrosarcoma; Ketolysis; Starvation; β-hydroxybutyrate dehydrogenase 2 (BDH2)

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30212
medRxiv. 2024 Apr 18. pii: 2024.04.16.24305925. [Epub ahead of print]

A randomized open-label, observational study of the novel ketone ester, bis octanoyl (R)-1,3-butanediol, and its acute effect on ß-hydroxybutyrate and glucose concentrations in healthy older adults.

Elizabeth B Stephens, Chatura Senadheera, Stephanie Roa-Diaz, Sawyer Peralta, Laura Alexander, Wendie Silverman-Martin, Michi Yukawa, Jenifer Morris, James B Johnson, John C Newman, Brianna J Stubbs.

Bis-octanoyl (R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentrations rapidly after ingestion. KE is hypothesized to have beneficial metabolic effects on health and performance, especially in older adults. Whilst many studies have investigated the ketogenic effect of KE in young adults, they have not been studied in an exclusively older adult population, for whom age-related differences in body composition and metabolism may alter the effects. This randomized, observational, open-label study in healthy older adults (n = 30, 50% male, age = 76.5 years, BMI = 25.2 kg/m 2 ) aimed to elucidate acute tolerance, blood BHB and blood glucose concentrations for 4 hours following consumption of either 12.5 or 25 g of BO-BD formulated firstly as a ready-to-drink beverage (n = 30), then as a re-constituted powder (n = 21), taken with a standard meal. Both serving sizes and formulations of BO-BD were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥ 0.5mM) that lasted until the end of the study. Ketosis was dose responsive; peak BHB concentration (C max ) and incremental area under the curve (iAUC) were significantly greater with 25 g compared to 12.5 g of BO-BD in both formulations. There were no significant differences in C max or iAUC between formulations. Blood glucose increased in all conditions following the meal; there were no consistent significant differences in glucose response between conditions. These results demonstrate that both powder and beverage formulations of the novel KE, BO-BD, induce ketosis in healthy older adults, facilitating future research on functional effects of this ingredient in aging.

DOI: https://doi.org/10.1101/2024.04.16.24305925
Trends Endocrinol Metab. 2024 Apr 29. pii: S1043-2760(24)00088-2. [Epub ahead of print]

MCU genetically altered mice suggest how mitochondrial Ca2+ regulates metabolism.

Jiuzhou Huo, Jeffery D Molkentin.

  Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca2+ increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca2+ uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca2+ uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca2+ uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca2+ regulates metabolism.

Keywords:  Ca(2+) signaling; metabolism; mitochondria; obesity; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2024.04.005
Cardiovasc Diabetol. 2024 Apr 27. 23(1): 145

Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial.

Faisal Aziz, Norbert J Tripolt, Peter N Pferschy, Hubert Scharnagl, Mahmoud Abdellatif, Abderrahim Oulhaj, Martin Benedikt, Ewald Kolesnik, Dirk von Lewinski, Harald Sourij.

  BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium.METHODS: This post hoc analysis of the EMMY trial investigated the changes in serum β-hydroxybutyrate (3-βOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-βOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio).
RESULTS: The mean 3-βOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-βOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-βOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-βOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-βOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant.
CONCLUSION: This post hoc analysis showed that SGLT2i increased 3-βOHB levels after AMI compared to placebo. Higher baseline 3-βOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-βOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-βOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

Keywords:  3-βOHB; Beta-hydroxybutyrate; Clinical Trial; Empagliflozin; Ketone body; SGLT2 inhibitor

DOI:  https://doi.org/10.1186/s12933-024-02221-2
Front Pharmacol. 2024 ;15 1368835

NLRP3 inflammasome and pyroptosis in cardiovascular diseases and exercise intervention.

Ping Ding, Yuanming Song, Yang Yang, Cheng Zeng.

  NOD-like receptor protein 3 (NLRP3) inflammasome is an intracellular sensing protein complex that possesses NACHT, leucine-rich repeat, and pyrin domain, playing a crucial role in innate immunity. Activation of the NLRP3 inflammasome leads to the production of pro-inflammatory cellular contents, such as interleukin (IL)-1β and IL-18, and induction of inflammatory cell death known as pyroptosis, thereby amplifying or sustaining inflammation. While a balanced inflammatory response is beneficial for resolving damage and promoting tissue healing, excessive activation of the NLRP3 inflammasome and pyroptosis can have harmful effects. The involvement of the NLRP3 inflammasome has been observed in various cardiovascular diseases (CVD). Indeed, the NLRP3 inflammasome and its associated pyroptosis are closely linked to key cardiovascular risk factors including hyperlipidemia, diabetes, hypertension, obesity, and hyperhomocysteinemia. Exercise compared with medicine is a highly effective measure for both preventing and treating CVD. Interestingly, emerging evidence suggests that exercise improves CVD and inhibits the activity of NLRP3 inflammasome and pyroptosis. In this review, the activation mechanisms of the NLRP3 inflammasome and its pathogenic role in CVD are critically discussed. Importantly, the purpose is to emphasize the crucial role of exercise in managing CVD by suppressing NLRP3 inflammasome activity and proposes it as the foundation for developing novel treatment strategies.

Keywords:  NLRP3 inflammasome; cardiovascular disease; exercise; intervation; pyroptosis

DOI:  https://doi.org/10.3389/fphar.2024.1368835
J Hum Kinet. 2024 Mar;91(Spec Issue): 225-244

Not Only Protein: Dietary Supplements to Optimize the Skeletal Muscle Growth Response to Resistance Training: The Current State of Knowledge.

Antonio Paoli, Giuseppe Cerullo, Antonino Bianco, Marco Neri, Federico Gennaro, Davide Charrier, Tatiana Moro.

  Regarding skeletal muscle hypertrophy, resistance training and nutrition, the most often discussed and proposed supplements include proteins. Although, the correct amount, quality, and daily distribution of proteins is of paramount importance for skeletal muscle hypertrophy, there are many other nutritional supplements that can help and support the physiological response of skeletal muscle to resistance training in terms of muscle hypertrophy. A healthy muscle environment and a correct whole muscle metabolism response to the stress of training is a prerequisite for the increase in muscle protein synthesis and, therefore, muscle hypertrophy. In this review, we discuss the role of different nutritional supplements such as carbohydrates, vitamins, minerals, creatine, omega-3, polyphenols, and probiotics as a support and complementary factors to the main supplement i.e., protein. The different mechanisms are discussed in the light of recent evidence.

Keywords:  ergogenic aids; muscle hypertrophy; strength training

DOI:  https://doi.org/10.5114/jhk/18666
Physiol Rep. 2024 May;12(9): e16025

Obesity-induced skeletal muscle remodeling: A comparative analysis of exercise training and ACE-inhibitory drug in male mice.

Ana Beatriz Proença, Beatriz Alexandre-Santos, Isabele Gomes Giori, Jaime Silva Filho Alex-Marques, Clarice Machado-Santos, Marcus Machado, D'Angelo Carlo Magliano, Antonio Claudio Lucas da Nobrega, Eliete Dalla Corte Frantz.

  Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

Keywords:  enalapril; exercise training; obesity; renin–angiotensin system; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.16025
J Am Heart Assoc. 2024 Apr 30. e033744

Short-Chain Fatty Acid Butyrate Is an Inotropic Agent With Vasorelaxant and Cardioprotective Properties.

Jacob Marthinsen Seefeldt, Casper Homilius, Jakob Hansen, Thomas Ravn Lassen, Nichlas Riise Jespersen, Rebekka Vibjerg Jensen, Ebbe Boedtkjer, Hans Erik Bøtker, Roni Nielsen.

  BACKGROUND: The heart can metabolize the microbiota-derived short-chain fatty acid butyrate. Butyrate may have beneficial effects in heart failure, but the underlying mechanisms are unknown. We tested the hypothesis that butyrate elevates cardiac output by mechanisms involving direct stimulation of cardiac contractility and vasorelaxation in rats.METHODS AND RESULTS: We examined the effects of butyrate on (1) in vivo hemodynamics using parallel echocardiographic and invasive blood pressure measurements, (2) isolated perfused hearts in Langendorff systems under physiological conditions and after ischemia and reperfusion, and (3) isolated coronary arteries mounted in isometric wire myographs. We tested Na-butyrate added to injection solutions or physiological buffers and compared its effects with equimolar doses of NaCl. Butyrate at plasma concentrations of 0.56 mM increased cardiac output by 48.8±14.9%, stroke volume by 38.5±12.1%, and left ventricular ejection fraction by 39.6±6.2%, and lowered systemic vascular resistance by 33.5±6.4% without affecting blood pressure or heart rate in vivo. In the range between 0.1 and 5 mM, butyrate increased left ventricular systolic pressure by up to 23.7±3.4% in isolated perfused hearts and by 9.4±2.9% following ischemia and reperfusion, while reducing myocardial infarct size by 81.7±16.9%. Butyrate relaxed isolated coronary septal arteries concentration dependently with an EC50=0.57 mM (95% CI, 0.23-1.44).
CONCLUSIONS: We conclude that butyrate elevates cardiac output through mechanisms involving increased cardiac contractility and vasorelaxation. This effect of butyrate was not associated with adverse myocardial injury in damaged hearts exposed to ischemia and reperfusion.

Keywords:  butyrate; contractile function; hemodynamics; metabolism; short‐chain fatty acids; vasorelaxation

DOI:  https://doi.org/10.1161/JAHA.123.033744
Sci Rep. 2024 04 30. 14(1): 9936

Mitochondrial dynamics: updates and perspectives.

Kezhong Zhang, Ježek Petr.

DOI: https://doi.org/10.1038/s41598-024-59998-1
Neurol Sci. 2024 Apr 27.

Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches.

Gokhan Burcin Kubat, Pasquale Picone.

  Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease that results in the loss of motor neurons and severe skeletal muscle atrophy. The etiology of ALS is linked to skeletal muscle, which can activate a retrograde signaling cascade that destroys motor neurons. This is why satellite cells and mitochondria play a crucial role in the health and performance of skeletal muscles. This review presents current knowledge on the involvement of mitochondrial dysfunction, skeletal muscle atrophy, muscle satellite cells, and neuromuscular junction (NMJ) in ALS. It also discusses current therapeutic strategies, including exercise, drugs, stem cells, gene therapy, and the prospective use of mitochondrial transplantation as a viable therapeutic strategy.

Keywords:  Amyotrophic lateral sclerosis; Mitochondria; Mitochondrial transplantation; Skeletal muscle dysfunction

DOI:  https://doi.org/10.1007/s10072-024-07508-6
Science. 2024 May 03. 384(6695): 563-572

Brain-muscle communication prevents muscle aging by maintaining daily physiology.

Arun Kumar, Mireia Vaca-Dempere, Thomas Mortimer, Oleg Deryagin, Jacob G Smith, Paul Petrus, Kevin B Koronowski, Carolina M Greco, Jessica Segalés, Eva Andrés, Vera Lukesova, Valentina M Zinna, Patrick-Simon Welz, Antonio L Serrano, Eusebio Perdiguero, Paolo Sassone-Corsi, Salvador Aznar Benitah, Pura Muñoz-Cánoves.

A molecular clock network is crucial for daily physiology and maintaining organismal health. We examined the interactions and importance of intratissue clock networks in muscle tissue maintenance. In arrhythmic mice showing premature aging, we created a basic clock module involving a central and a peripheral (muscle) clock. Reconstituting the brain-muscle clock network is sufficient to preserve fundamental daily homeostatic functions and prevent premature muscle aging. However, achieving whole muscle physiology requires contributions from other peripheral clocks. Mechanistically, the muscle peripheral clock acts as a gatekeeper, selectively suppressing detrimental signals from the central clock while integrating important muscle homeostatic functions. Our research reveals the interplay between the central and peripheral clocks in daily muscle function and underscores the impact of eating patterns on these interactions.

DOI: https://doi.org/10.1126/science.adj8533