A Critical Appraisal of the Tafazzin Knockdown Mouse Model of Barth Syndrome: What Have We Learned About Pathogenesis and Potential Treatments?

A Critical Appraisal of the Tafazzin Knockdown Mouse Model of Barth Syndrome: What Have We Learned About Pathogenesis and Potential Treatments? Am J Physiol Heart Circ Physiol. 2019 Oct 11;: Authors: Ren M, Miller PC, Schlame M, Phoon CKL Abstract Pediatric heart failure remains poorly understood, distinct in many aspects from adult heart failure. Limited data point to roles of altered mitochondrial functioning and in particular, changes in mitochondrial lipids, especially cardiolipin. Barth syndrome is a mitochondrial disorder caused by tafazzin mutations that lead to abnormal cardiolipin profiles. Patients are afflicted by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay. A mouse model of Barth syndrome was developed a decade ago, which relies on a doxycycline-inducible shRNA to knock down expression of tafazzin mRNA ("TAZKD"). Our objective was to review published data from the TAZKD mouse to determine its contributions to our pathogenetic understanding of, and potential treatment strategies for, Barth syndrome. In regard to the clinical syndrome, the reported physiological, biochemical, and ultrastructural abnormalities of the mouse model mirror those in Barth patients. Using this model, the PPAR pan-agonist bezafibrate has been suggested as potential therapy because it ameliorated the cardiomyopathy in TAZKD mice, while increasing mitochondrial biogenesis. A clinical trial is now underway to test bezafibrate in Barth syndro...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Tags: Am J Physiol Heart Circ Physiol Source Type: research

Related Links:

Abstract Sarcopenia, obesity and their coexistence, obese sarcopenia (OBSP) as well as atherosclerosis-related cardio-vascular diseases (ACVDs), including chronic heart failure (CHF), are among the greatest public health concerns in the ageing population. A clear age-dependent increased prevalence of sarcopenia and OBSP has been registered in CHF patients, suggesting mechanistic relationships. Development of OBSP could be mediated by a crosstalk between the visceral and subcutaneous adipose tissue (AT) and the skeletal muscle under conditions of low-grade local and systemic inflammation, inflammaging. The present ...
Source: Ageing Research Reviews - Category: Genetics & Stem Cells Authors: Tags: Ageing Res Rev Source Type: research
ConclusionsWe describe a unique and novel cellular model that provides insight into the mitochondrial abnormalities present in DCMA and identifies SS-31 as a potential therapeutic for this devastating disease.
Source: Canadian Journal of Cardiology - Category: Cardiology Source Type: research
Publication date: Available online 3 October 2019Source: Molecular Aspects of MedicineAuthor(s): Pablo E. Morales, Carla Arias-Durán, Yáreni Ávalos-Guajardo, Geraldine Aedo, Hugo E. Verdejo, Valentina Parra, Sergio LavanderoAbstractHealthy mitochondrial function is imperative for most tissues, but especially those with a high energy demand. Robust evidence linking mitochondrial dysfunction with cardiovascular disease has demonstrated that mitochondrial activity is highly relevant to cardiac muscle performance. Mitochondrial homeostasis is maintained through coordination among the processes that compris...
Source: Molecular Aspects of Medicine - Category: Molecular Biology Source Type: research
In conclusion, with study of the frailty syndrome still in its infancy, frailty analysis remains a major challenge. It is a challenge that needs to be overcome in order to shed light on the multiple mechanisms involved in the pathogenesis of this syndrome. Although several mechanisms contribute to frailty, immune system alteration seems to play a central role: this syndrome is characterized by increased levels of pro-inflammatory markers and the resulting pro-inflammatory status can have negative effects on various organs. Future studies should aim to better clarify the immune system alteration in frailty, and seek to esta...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Abstract Diabetes mellitus (DM) has become an increasingly common disease with high disability and mortality rates. Diabetes complications are the main cause of diabetes death and about 50% of diabetic patients died from heart disease in developed countries reported by World Health Organization. Diabetic cardiomyopathy (DCM) has been considered as a high incidence and serious complication of DM and plays a key role in the incidence and development of diabetes related heart failure. Metabolism dysregulation is regarded as an important and earlier factor occurred in the pathogenesis of DCM. Insulin resistance, oxida...
Source: Current Protein and Peptide Science - Category: Biochemistry Authors: Tags: Curr Protein Pept Sci Source Type: research
The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) was first identified in 1998 as a PGC-1 family member that regulates adaptive thermogenesis and mitochondrial function following cold exposure in brown adipose tissue. The PGC-1 family has drawn widespread attention over the past two decades as the energetic regulator. We recently summarized a review regarding PGC-1 signaling pathway and its mechanisms in cardiac metabolism. In this review, we elaborate upon the PGC-1 signaling network and highlight the recent progress of its versatile roles in cardiac diseases, includi...
Source: Theranostics - Category: Molecular Biology Authors: Tags: Review Source Type: research
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study, we report the age-associated differences between fetal MSC (fMSC) populations and MSCs isolated from elderly donors with respect to their transcriptomes. We successfully reprogrammed fMSCs (55 days post conception) and adult MSC (aMSC; 60-74 years) to iPSCs and, subsequently, generated the corresponding iMSCs. In addition, iMSCs were also derived from ESCs. The iMSCs were similar although not identical to primary MSCs. We unraveled a putative rejuvenation and aging gene expression signature. We show that iMSCs irrespective of donor age and cell type re-acquired a similar secretome to that of th...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In conclusion, FGF21 belongs to a promising class of cytokines that are induced in response to stress and that can be used as a drug, drug target, or through a biomarker, depending on the physio-pathological context. All these findings will become clear when FGF21 will be used as a therapeutic molecule, exploiting the beneficial effects of FGF21 for treating metabolic disease or when it will be blocked to ameliorate disease progression and the onset of disease. Author Contributions CT and MS wrote the manuscript. VR contributed to the discussion. Funding This work was supported from the AFM-Telethon (19524), Italian Mi...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Conclusion Myocardial energy metabolism is a complex process, which consists of a network of biochemical reactions and pathways. The initial stage is energy substrate utilization due to its uptake and metabolism as well as following participation of intermediates in TCA cycle. Then mitochondrial oxidative phosphorylation enables generation of ATP molecules, and finally, the creatine kinase system transports ATP from mitochondria to the sarcomeres. In the light of the foregoing evidence, metabolism of the heart subjected to pressure overload may be disturbed in all of this areas. In spite of differences among humans and an...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
More News: Cardiology | Cardiomyopathy | Clinical Trials | Doxycycline | Heart | Heart Failure | Mitochondrial Disease | Pediatrics | Physiology