bims-kimdis 2024-07-28 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒07‒28
fifteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

A New Nomenclature for the Very Low-Calorie Ketogenic Diet (VLCKD): Very Low-Energy Ketogenic Therapy (VLEKT). Ketodiets and Nutraceuticals Expert Panels: "KetoNut", Italian Society of Nutraceuticals (SINut) and the Italian Association of Dietetics and Clinical Nutrition (ADI).
A three-week ketogenic diet increases skeletal muscle insulin sensitivity in individuals with obesity - a randomized, controlled crossover trial.
Effects of the Ketogenic Diet on Strength Performance in Trained Men and Women: A Systematic Review and Meta-Analysis.
Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing.
Linking mitochondrial dysfunction, neurotransmitter, neural network abnormalities and mania: Elucidating neurobiological mechanisms of the therapeutic effect of the ketogenic diet in Bipolar Disorder.
Ketogenic diet benefits in critically ill patients with sepsis.
Ring around the mitochondria.
β-Hydroxybutyrate Improves the Redox Status, Cytokine Production and Phagocytic Potency of Glucose-Deprived HMC3 Human Microglia-like Cells.
Efficacy and Safety of Exogenous Ketones in People with Mild Neurocognitive Disorder and Alzheimer's Disease: A Systematic Literature Review.
Accuracy of a continuous glucose monitoring system applied before, during, and after an intense leg-squat session with low- and high-carbohydrate availability in young adults without diabetes.
The Role of Branched Chain Ketoacid Dehydrogenase Kinase (BCKDK) in Skeletal Muscle Biology and Pathogenesis.
Metabolic flexibility and resting autonomic function in active menopausal women.
Suppression of inflammatory macrophages reduces atherosclerosis.
Effects of Oral Butyrate on Blood Pressure in Patients With Hypertension: A Randomized, Placebo-Controlled Trial.
Cardiomyopathy in Duchenne Muscular Dystrophy and the Potential for Mitochondrial Therapeutics to Improve Treatment Response.

Curr Nutr Rep. 2024 Jul 23.

A New Nomenclature for the Very Low-Calorie Ketogenic Diet (VLCKD): Very Low-Energy Ketogenic Therapy (VLEKT). Ketodiets and Nutraceuticals Expert Panels: "KetoNut", Italian Society of Nutraceuticals (SINut) and the Italian Association of Dietetics and Clinical Nutrition (ADI).

Luigi Barrea, Massimiliano Caprio, Davide Grassi, Arrigo Francesco Giuseppe Cicero, Carmela Bagnato, Barbara Paolini, Giovanna Muscogiuri.

  PURPOSE OF REVIEW: In an attempt to clarify the most appropriate nomenclature for the very low-calorie ketogenic diets (VLCKD), we propose to change the nomenclature and acronym of this medical nutrition therapy. The new definition and acronym proposed by the "KetoNut" panel of experts of the Italian Society of Nutraceuticals (SINut) and the Italian Association of Dietetics and Clinical Nutrition (ADI) is Very Low-Energy Ketogenic Therapy (VLEKT).RECENT FINDINGS: In the last few years, different authors have focused on the issue of confusion in the nomenclature of ketogenic diets. In detail, have been differentiated the VLCKD that provides < 800 kcal per day, which is intended for the weight loss in the medical treatment of obesity, and a eucaloric ketogenic diet, which contains more calories from fat (predominantly unsaturated) and with specific ketogenic ratios, for allow growth in children while helping, at the same time, to establish epileptic seizure control. In recent years, ketogenic diets have attracted great interest for their efficacy in the treatment of epilepsy and other neurological diseases but also in patients with overweight and obesity-related metabolic disorders. Nevertheless, although ketogenic diets are a dietary intervention designed to induce nutritional ketosis, different diets with different macronutrients' composition have been called with this name. The confusion in the nomenclature of ketogenic diets may result in significant bias and mistakes in the interpretation of the current scientific evidence.

Keywords:  Ketogenic diet; Nomenclature; Obesity; Very low calorie ketogenic diets VLCKD; Very low energy ketogenic therapy

DOI:  https://doi.org/10.1007/s13668-024-00560-w
Diabetes. 2024 Jul 25. pii: db240162. [Epub ahead of print]

A three-week ketogenic diet increases skeletal muscle insulin sensitivity in individuals with obesity - a randomized, controlled crossover trial.

Thien Vinh Luong, Mette Glavind Bülow Pedersen, Caroline Bruun Abild, Katrine Meyer Lauritsen, Mette Louise Gram Kjærulff, Niels Møller, Lars Christian Gormsen, Esben Søndergaard.

A ketogenic diet (KD) can induce weight loss and improve glycemic regulation, potentially reducing the risk of developing type 2 diabetes. To elucidate the underlying mechanisms behind these beneficial effects of a KD, we investigated the impact of a KD on organ-specific insulin sensitivity (IS) in skeletal muscle, liver, and adipose tissue. We hypothesized that a KD would increase IS in skeletal muscle. The study included 11 individuals with obesity who underwent a randomized, crossover trial with two three-week interventions: 1) KD and 2) standard diet. Skeletal muscle IS was quantified as the increase in glucose disposal during a hyperinsulinemic-euglycemic clamp (HEC). Hepatic IS and adipose tissue IS were quantified as the relative suppression of endogenous glucose production (EGP) and the relative suppression of palmitate flux during the HEC. The KD led to a 2.2 kg weight loss, increased insulin-stimulated glucose disposal, whereas the relative suppression of EGP during the HEC was similar. In addition, the KD decreased insulin-mediated suppression of lipolysis. In conclusion, a KD increased skeletal muscle IS in individuals with obesity.

DOI: https://doi.org/10.2337/db24-0162
Nutrients. 2024 Jul 10. pii: 2200. [Epub ahead of print]16(14):

Effects of the Ketogenic Diet on Strength Performance in Trained Men and Women: A Systematic Review and Meta-Analysis.

Salvador Vargas-Molina, Mora Murri, Andrés Gonzalez-Jimenez, José Luis Gómez-Urquiza, Javier Benítez-Porres.

  Ketogenic diets (KDs) are an alternative to improve strength performance and body composition in resistance training participants. The objective of this review and meta-analysis is to verify whether a ketogenic diet produces an increase in the strength of resistance-trained participants. We have evaluated the effect of the ketogenic diet in conjunction with resistance training on the strength levels in trained participants. Boolean algorithms from various databases (PubMed, Scopus, and Web of Science) were used. Meta-analyses were carried out, one on the 1-RM squat (SQ), with 106 trained participants or athletes, and another on the 1-RM on the bench press (BP), evaluating 119 participants. We did not find significant differences between the groups in the variables of SQ or BP, although the size of the effect was slightly higher in the ketogenic group. Conclusions: KDs do not appear to impair 1-RM performance; however, this test does not appear to be the most optimal tool for assessing hypertrophy-based strength session performance in resistance-trained participants.

Keywords:  carbohydrate restriction; ketosis; performance; repetition maximum; resistance-training; strength parameters

DOI:  https://doi.org/10.3390/nu16142200
Sports Med. 2024 Jul 26.

Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing.

Sophie C Broome, Jamie Whitfield, Leonidas G Karagounis, John A Hawley.

The age-related loss of skeletal muscle mass and physical function leads to a loss of independence and an increased reliance on health-care. Mitochondria are crucial in the aetiology of sarcopenia and have been identified as key targets for interventions that can attenuate declines in physical capacity. Exercise training is a primary intervention that reduces many of the deleterious effects of ageing in skeletal muscle quality and function. However, habitual levels of physical activity decline with age, making it necessary to implement adjunct treatments to maintain skeletal muscle mitochondrial health and physical function. This review provides an overview of the effects of ageing and exercise training on human skeletal muscle mitochondria and considers several supplements that have plausible mechanistic underpinning to improve physical function in ageing through their interactions with mitochondria. Several supplements, including MitoQ, urolithin A, omega-3 polyunsaturated fatty acids (n3-PUFAs), and a combination of glycine and N-acetylcysteine (GlyNAC) can improve physical function in older individuals through a variety of inter-dependent mechanisms including increases in mitochondrial biogenesis and energetics, decreases in mitochondrial reactive oxygen species emission and oxidative damage, and improvements in mitochondrial quality control. While there is evidence that some nicotinamide adenine dinucleotide precursors can improve physical function in older individuals, such an outcome seems unrelated to and independent of changes in skeletal muscle mitochondrial function. Future research should investigate the safety and efficacy of compounds that can improve skeletal muscle health in preclinical models through mechanisms involving mitochondria, such as mitochondrial-derived peptides and mitochondrial uncouplers, with a view to extending the human health-span.

DOI: https://doi.org/10.1007/s40279-024-02072-7
Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 Jul 23. pii: S2451-9022(24)00199-X. [Epub ahead of print]

Linking mitochondrial dysfunction, neurotransmitter, neural network abnormalities and mania: Elucidating neurobiological mechanisms of the therapeutic effect of the ketogenic diet in Bipolar Disorder.

Zachary Freyberg, Ana C Andreazza, Colleen A McClung, Mary L Phillips.

  There is growing interest in the ketogenic diet as a treatment for Bipolar Disorder (BD), with promising anecdotal and small case study reports of efficacy. Yet, the neurobiological mechanisms by which diet-induced ketosis might ameliorate BD symptoms remain to be determined, particularly in manic and hypomanic states - defining features of BD. Identifying these mechanisms will therefore provide new markers to guide personalized interventions and provide targets for novel treatment developments for individuals with BD. In this critical review, we describe recent findings highlighting two types of neurobiological abnormalities in BD: 1) mitochondrial dysfunction; and 2) neurotransmitter and neural network functional abnormalities. We will consequently link these abnormalities lead to mania/hypomania and depression in BD and then describe the biological underpinnings by which the ketogenic diet might have a beneficial effect in individuals with BD. We end the review by describing future approaches that can be employed to elucidate the neurobiology underlying the therapeutic effect of the ketogenic diet in BD. In so doing, this may provide marker predictors to identify individuals who will respond well to the ketogenic diet, as well as offer neural targets for novel treatment developments for BD.

Keywords:  Bipolar Disorder; Dopamine; Ketogenic Diet; Metabolism; Mitochondria; Neural Network

DOI:  https://doi.org/10.1016/j.bpsc.2024.07.011
Nat Rev Nephrol. 2024 Jul 24.

Ketogenic diet benefits in critically ill patients with sepsis.

Monica Wang.

DOI: https://doi.org/10.1038/s41581-024-00877-3
Sci Signal. 2024 Jul 23. 17(846): eadr8314

Ring around the mitochondria.

Wei Wong.

Hexokinase 1 forms constricting rings around mitochondria that prevent fission induced by energy stress.

DOI: https://doi.org/10.1126/scisignal.adr8314
J Neuroimmune Pharmacol. 2024 Jul 23. 19(1): 35

β-Hydroxybutyrate Improves the Redox Status, Cytokine Production and Phagocytic Potency of Glucose-Deprived HMC3 Human Microglia-like Cells.

Anil Kumar Rana, Babita Bhatt, Mohit Kumar.

  Brain glucose deprivation is a component of the pathophysiology of ischemia, glucose transporter1 (GLUT1) deficiency, neurological disorders and occurs transiently in diabetes. Microglia, the neuroimmune cells must function effectively to offer immune defence and debris removal in low-energy settings. Brain glucose deprivation may compromise microglial functions further escalating the disease pathology and deteriorating the overall mental health. In the current study, HMC3 human microglia-like cells were cultured in vitro and exposed to glucose deprivation to investigate the effects of glucose deprivation on phenotypic state, redox status, secretion of cytokines and phagocytic capabilities of HMC3 cells. However, HMC3 cells were able to proliferate in the absence of glucose but showed signs of redox imbalance and mitochondrial dysfunction, as demonstrated by decreased MTT reduction and Mito Tracker™ staining of cells, along with a concomitant reduction in NOX2 protein, superoxide, and nitrite levels. Reduced levels of secreted TNF and IL-1β were the signs of compromised cytokine secretion by glucose-deprived HMC3 microglia-like cells. Moreover, glucose-deprived HMC3 cells also showed reduced phagocytic activity as assessed by fluorescently labelled latex beads-based functional phagocytosis assay. β-hydroxybutyrate (BHB) supplementation restored the redox status, mitochondrial health, cytokine secretion, and phagocytic activity of glucose-deprived HMC3 microglia-like cells. Overall, impaired brain glucose metabolism may hinder microglia's capacity to release diffusible immune factors and perform phagocytosis. This could escalate the mental health issues in neurological diseases where brain glucose metabolism is compromised. Moreover, nutritional ketosis or exogenous ketone supplementation such as BHB may be utilized as a potential metabolic therapies for these conditions.

Keywords:  Cytokines; Glucose deprivation; HMC3; Human microglia; Phagocytosis; β-Hydroxybutyrate

DOI:  https://doi.org/10.1007/s11481-024-10139-5
Nutr Rev. 2024 Jul 24. pii: nuae098. [Epub ahead of print]

Efficacy and Safety of Exogenous Ketones in People with Mild Neurocognitive Disorder and Alzheimer's Disease: A Systematic Literature Review.

Pierre Krolak-Salmon, Russell H Swerdlow, Thibault Mastain, Catherine Dive-Pouletty, Nick Pooley, Masoumeh Kisomi.

  CONTEXT: Mild neurocognitive disorder (NCD), formally known as mild cognitive impairment, is usually the clinical stage preceding the development of Alzheimer's disease (AD), the most prevalent major NCD, and other causes of dementia. Glucose is a major source of energy for human brain metabolism and the uptake of glucose is reduced in patients with mild NCD, AD, and other NCDs. Unlike glucose, the uptake of ketones remains normal in people with mild NCD and AD, suggesting that the use of ketone bodies may compensate for glucose energy deficiency in patients with mild NCD and AD.OBJECTIVE: The aim of this systematic review was to summarize the efficacy and safety of exogenic ketones, including medium chain triglycerides (MCTs), on cognitive function in patients with mild NCD and AD.
DATA SOURCES: The Embase, MEDLINE, MEDLINE In-Process, PubMed Ahead-of-Print, Cochrane Central Register of Controlled Trials, Europe PMC databases were searched from inception to April 2022. Studies reporting cognitive function efficacy and safety outcomes from randomized controlled trials of exogenic ketones in patients with mild NCD and AD were included.
DATA EXTRACTION: Data were extracted by 1 reviewer and checked by a second reviewer. Risk of bias was assessed using the Cochrane risk of bias tool, version 2.
DATA ANALYSIS: This review identified 13 individual trials investigating the efficacy and safety of MCT or coconut oil for patients with mild NCD or with AD. Because of the heterogeneity of the studies, a narrative synthesis was used.
CONCLUSION: Overall, improvements associated with exogenic ketones were observed in multiple aspects of cognitive abilities, although the large heterogeneity between the included studies makes it difficult to draw firm conclusions from the current literature. Although some studies investigated the impact of the apolipoprotein E ε4 allele status on treatment efficacy, the current data are insufficient to conclude whether such an effect is present.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No. CRD42022336664.

Keywords:  Alzheimer’s disease; cognitive function; exogenic ketones; medium chain triglycerides; mild neurocognitive disorder

DOI:  https://doi.org/10.1093/nutrit/nuae098
Eur J Appl Physiol. 2024 Jul 22.

Accuracy of a continuous glucose monitoring system applied before, during, and after an intense leg-squat session with low- and high-carbohydrate availability in young adults without diabetes.

Manuel Matzka, Niels Ørtenblad, Mascha Lenk, Billy Sperlich.

  PURPOSE: The aim was to assess the accuracy of a continuous blood glucose monitoring (CGM) device (Abbott FreeStyle Libre 3) against capillary blood glucose measurement (BGM) before, during, and after an intense lower body strength training session in connection with high- versus low-carbohydrate breakfasts.METHODS: Nine adults (22 ± 2 years) completed a strength training session (10 × 10 at 60% 1RM) twice after high-carbohydrate and twice after low-carbohydrate breakfasts. CGM accuracy versus BGM was assessed across four phases: post-breakfast, pre-exercise, exercise, and post-exercise.
RESULTS: Overall fed state mean BGM levels were 84.4 ± 20.6 mg/dL. Group-level Bland-Altman analysis showed acceptable agreement between CGM and BGM across all phases, with mean biases between - 7.95 and - 17.83 mg/dL; the largest discrepancy was in the post-exercise phase. Mean absolute relative difference was significantly higher post-exercise compared to pre-exercise and exercise phases, for overall data and after the high-carbohydrate breakfast (all p ≤ 0.02). Clark Error Grid analysis showed 50.5-64.3% in Zone A and 31.7-44.6% in Zone B, with an increase in treatment errors during and after exercise.
CONCLUSION: In this group of healthy participants undergoing strength training, CGM showed satisfactory accuracy in glucose monitoring but varied substantially between individuals compared to BGM and fails in meeting clinical criteria for diabetic monitoring. CGM could aid non-diabetic athletes by tracking glucose fluctuations due to diet and exercise. Although utilization of CGM shows potential in gathering, analyzing, and interpreting interstitial glucose for improving performance, the application in sports nutrition is not yet validated, and challenges in data interpretation could limit its adoption.

Keywords:  Metabolism; Nutrition; Strength training; Technology

DOI:  https://doi.org/10.1007/s00421-024-05557-5
Int J Mol Sci. 2024 Jul 11. pii: 7601. [Epub ahead of print]25(14):

The Role of Branched Chain Ketoacid Dehydrogenase Kinase (BCKDK) in Skeletal Muscle Biology and Pathogenesis.

Joshua Fernicola, Sagar Vyavahare, Sonu Kumar Gupta, Aditya Kalwaghe, Kate Kosmac, Adam Davis, Matthew Nicholson, Carlos M Isales, Rahul Shinde, Sadanand Fulzele.

  Muscle wasting can be caused by nutrition deficiency and inefficient metabolism of amino acids, including Branched Chain Amino Acids (BCAAs). Branched Chain Amino Acids are a major contributor to the metabolic needs of healthy muscle and account for over a tenth of lean muscle mass. Branched chain alpha-ketoacid dehydrogenase (BCKD) is the rate limiting enzyme of BCAA metabolism. Inhibition of BCKD is achieved through a reversible phosphorylation event by Branched Chain a-ketoacid dehydrogenase kinase (BCKDK). Our study set out to determine the importance of BCKDK in the maintenance of skeletal muscle. We used the Gene Expression Omnibus Database to understand the role of BCKDK in skeletal muscle pathogenesis, including aging, muscular disease, and interrupted muscle metabolism. We found BCKDK expression levels were consistently decreased in pathologic conditions. These results were most consistent when exploring muscular disease followed by aging. Based on our findings, we hypothesize that decreased BCKDK expression alters BCAA catabolism and impacts loss of normal muscle integrity and function. Further research could offer valuable insights into potential therapeutic strategies for addressing muscle-related disorders.

Keywords:  BCKDK; muscle pathogenesis; skeletal muscle

DOI:  https://doi.org/10.3390/ijms25147601
Eur J Appl Physiol. 2024 Jul 25.

Metabolic flexibility and resting autonomic function in active menopausal women.

Jordi Monferrer-Marín, Ainoa Roldán, Jørn Wulff Helge, Cristina Blasco-Lafarga.

  PURPOSE: The present study aims to analyze the relationship between cardiac autonomic control at rest-i.e., baseline Heart Rate Variability (HRV)-and metabolic flexibility assessed by means of the FATox and CHOox oxidation rates at the intensities of maximum fat and carbohydrate oxidation (MFO and MCO, respectively).METHODS: Twenty-four active over-60 women (66.8 ± 4.4 years) had their HRV assessed with 10 min recordings under resting conditions, and this was analyzed with Kubios Scientific software. After this, an incremental submaximal cycling test, starting at 30 watts, with increments of 10 watts every 3 min 15 s was performed. FATox and CHOox were calculated in the last 60 s at each step, using Frayn's equation. MFO and MCO were further obtained.
RESULTS: Nonlinear SampEn and 1-DFAα1 (Detrending Fluctuation Analysis score) at rest were both moderate and significantly (p < 0.05) related to FATox (r = 0.43, r = -0.40) and CHOox (r = -0.59, r = 0.41), as well as RER (r = -0.43, r = 0.43) at FATmax intensity. At the MCO intensity, no association was observed between HRV and oxidation rates. However, DFAα1 (r = -0.63, p < 0.05), the frequency ratio LF/HF (r = -0.63, p < 0.05), and the Poincaré ratio SD1/SD2 (r = 0.48, p < 0.05) were correlated with blood lactate concentration.
CONCLUSION: These results support the autonomic resources hypothesis, suggesting that better autonomic function at rest is related to enhanced metabolic flexibility in postmenopausal women. They also underpin a comprehensive analysis of cardiovascular-autonomic health with aging. The results imply that non-linear DFAα1 and SampEn are appropriate to analyze this association in health of the aging cardiovascular-autonomic system.

Keywords:  Autonomic nervous system; Blood lactate; DFAα1; Fat oxidation; Heart rate variability

DOI:  https://doi.org/10.1007/s00421-024-05568-2
J Physiol. 2024 Jul 26.

Suppression of inflammatory macrophages reduces atherosclerosis.

Srayasi Majee, Anushka Banerjee.



Keywords:  atherosclerosis; foam cells; inflammation; macrophages; proteoglycan

DOI:  https://doi.org/10.1113/JP287013
Hypertension. 2024 Jul 22.

Effects of Oral Butyrate on Blood Pressure in Patients With Hypertension: A Randomized, Placebo-Controlled Trial.

Barbara J H Verhaar, Madelief Wijdeveld, Koen Wortelboer, Elena Rampanelli, Johannes H M Levels, Didier Collard, Marianne Cammenga, Vanasa Nageswaran, Arash Haghikia, Ulf Landmesser, Xinmin S Li, Joseph A DiDonato, Stanley L Hazen, Ingrid M Garrelds, A H Jan Danser, Bert-Jan H van den Born, Max Nieuwdorp, Majon Muller.

  BACKGROUND: The microbiota-derived short chain fatty acid butyrate has been shown to lower blood pressure (BP) in rodent studies. Nonetheless, the net effect of butyrate on hypertension in humans remains uncovered. In this study, for the first time, we aimed to determine the effect of oral butyrate on BP in patients with hypertension.METHODS: We performed a double-blind randomized placebo-controlled trial including 23 patients with hypertension. Antihypertensive medication was discontinued for the duration of the study with a washout period of 4 weeks before starting the intervention. Participants received daily oral capsules containing either sodium butyrate or placebo with an equivalent dosage of sodium chloride for 4 weeks. The primary outcome was daytime 24-hour systolic BP. Differences between groups over time were assessed using linear mixed models (group-by-time interaction).
RESULTS: Study participants (59.0±3.7 years; 56.5% female) had an average baseline office systolic BP of 143.5±14.6 mm Hg and diastolic BP of 93.0±8.3 mm Hg. Daytime 24-hour systolic and diastolic BP significantly increased over the intervention period in the butyrate compared with the placebo group, with an increase of +9.63 (95% CI, 2.02-17.20) mm Hg in daytime 24-hour systolic BP and +5.08 (95% CI, 1.34-8.78) mm Hg in diastolic BP over 4 weeks. Butyrate levels significantly increased in plasma, but not in feces, upon butyrate intake, underscoring its absorption.
CONCLUSIONS: Four-week treatment with oral butyrate increased daytime systolic and diastolic BP in subjects with hypertension. Our findings implicate that butyrate does not have beneficial effects on human hypertension, which warrants caution in future butyrate intervention studies.
REGISTRATION: URL: https://clinicaltrialregister.nl/nl/trial/22936; Unique identifier: NL8924.

Keywords:  blood pressure; butyrates; feces; gastrointestinal microbiome; humans

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.123.22437
Cells. 2024 Jul 09. pii: 1168. [Epub ahead of print]13(14):

Cardiomyopathy in Duchenne Muscular Dystrophy and the Potential for Mitochondrial Therapeutics to Improve Treatment Response.

Shivam Gandhi, H Lee Sweeney, Cora C Hart, Renzhi Han, Christopher G R Perry.

  Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene, resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with the development of cardiomyopathy-the leading cause of death-inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD; treatment is aimed at delaying disease progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to the development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial dysfunction is thought to be a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but the effects of such agents on cardiac function remain unclear. The synergistic integration of small molecule- and gene-target-based drugs with metabolic-, immune-, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder.

Keywords:  Duchenne muscular dystrophy; antioxidants; bioenergetics; calcium balance; cardiomyopathy; elamipretide; gene therapy; inflammation; ion dysregulation; metabolism; mitochondria; reactive oxygen species; sarcolemmal tearing; skeletal muscle; therapy

DOI:  https://doi.org/10.3390/cells13141168