Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.
Mutations in amphiphysin-2/BIN1, dynamin 2, and myotubularin are associated with centronuclear myopathy (CNM), a muscle disorder characterized by myofibers with atypical central nuclear positioning and abnormal triads. Mis-splicing of amphiphysin-2/BIN1 is also associated with myotonic dystrophy that shares histopathological hallmarks with CNM. How amphiphysin-2 orchestrates nuclear positioning and triad organization and how CNM-associated mutations lead to muscle dysfunction remains elusive. We find that N-WASP interacts with amphiphysin-2 in myofibers and that this interaction and N-WASP distribution are disrupted by amphiphysin-2 CNM mutations. We establish that N-WASP functions downstream of amphiphysin-2 to drive peripheral nuclear positioning and triad organization during myofiber formation. Peripheral nuclear positioning requires microtubule/Map7/Kif5b-dependent distribution of nuclei along the myofiber and is driven by actin and nesprins. In adult myofibers, N-WASP and amphiphysin-2 are only involved in the maintenance of triad organization but not in the maintenance of peripheral nuclear positioning. Importantly, we confirmed that N-WASP distribution is disrupted in CNM and myotonic dystrophy patients. Our results support a role for N-WASP in amphiphysin-2-dependent nuclear positioning and triad organization and in CNM and myotonic dystrophy pathophysiology.
Evidence suggests that endothelin-1 (ET-1) plays an essential role in brain inflammation. However, whether ET-1 contributes directly to blood-brain barrier (BBB) breakdown remains to be elucidated. Using an in vitro BBB model consisting of co-cultures of human primary astrocytes and brain microvascular endothelial cells (BMVECs), we first investigated the expression of ET-1 by BMVECs upon stimulation with tumour necrosis factor (TNF)-a, which plays an essential role in the induction and synthesis of ET-1 during systemic inflammatory responses. Increased ET-1 mRNA was detected in the human BMVECs 24 h after TNF-a treatment. This was correlated with an increase in ET-1 levels in the culture medium, as determined by sandwich immunoassay. Both TNF-a and ET-1 increased the permeability of human BMVECs to a paracellular tracer, sucrose, but only in the presence of astrocytes.The increase in BMVEC permeability by TNF-a was partially prevented by antibody neutralization of ET-1 and completely by monoclonal antibody against IL-1b. Concomitantly, TNF-a induced IL-1b mRNA expression by astrocytes in co-culture and this effect was partially prevented by ET-1 antibody neutralization. In parallel experiments, treatment of human primary astrocytes in single cultures with ET-1 for 24 h induced IL-1b mRNA synthesis and IL-1b protein secretion in the cell culture supernatant. Taken together, these results provide evidence for paracrine actions involving ET-1, TNF-a and IL-1b between human astrocytes and BMVECs, which may play a central role in BBB breakdown during CNS inflammation. Keywords: blood-brain barrier, endothelin-1, interleukin-1b, neuropathogenesis, tumour necrosis factor-a. Endothelin-1 (ET-1) is a 21-amino-acid peptide considered to belong to the cytokine family. Isolated from endothelial cells, ET-1 has been found to be one of the most potent vasoconstrictor peptides in humans (Yanagisawa et al. 1988). In addition, ET-1 has been implicated as a mediator of cerebrovascular responses in ischaemic stroke and subarachnoid haemorrhage (Masaoka et al. 1989;Kohno et al. 1990;Suzuki et al. 1990;Yasuda et al. 1990;Lampl et al. 1997). ET-1 also exerts a wide spectrum of effects on non-vascular tissues, including those of the CNS. Recent evidence demonstrated the neuropathological significance of ET-1, as shown by the correlation between increased blood-brain barrier (BBB) permeability (Narushima et al. 1999;Chi et al. 2001), and increased ET-1 levels in CSF and CNS parenchyma (Rolinski et al. 1999), although its prime role in this process and the underlying mechanisms remain to be elucidated.The role of cytokines such as interleukin (IL)-1b and tumour necrosis factor (TNF)-a in the neuropathogenesis of brain inflammation is well established (Griffin et al. 1994;Boven et al. 1999). IL-1b has been shown to be associated with the pathophysiology of demyelinating disorders such as Abbreviations used: BBB, blood-brain barrier; BMVEC, brain microvascular endothelial cell; ELISA, enzyme-linked immunosorbent assay; ET-1, endo...
Environmental factors during early life are critical for the later metabolic health of the individual and of future progeny. In our obesogenic environment, it is of great socioeconomic importance to investigate the mechanisms that contribute to the risk of metabolic ill health. Imprinted genes, a class of functionally mono-allelic genes critical for early growth and metabolic axis development, have been proposed to be uniquely susceptible to environmental change. Furthermore, it has also been suggested that perturbation of the epigenetic reprogramming of imprinting control regions (ICRs) may play a role in phenotypic heritability following early life insults. Alternatively, the presence of multiple layers of epigenetic regulation may in fact protect imprinted genes from such perturbation. Unbiased investigation of these alternative hypotheses requires assessment of imprinted gene expression in the context of the response of the whole transcriptome to environmental assault. We therefore analyse the role of imprinted genes in multiple tissues in two affected generations of an established murine model of the developmental origins of health and disease using microarrays and quantitative RT–PCR. We demonstrate that, despite the functional mono-allelicism of imprinted genes and their unique mechanisms of epigenetic dosage control, imprinted genes as a class are neither more susceptible nor protected from expression perturbation induced by maternal undernutrition in either the F1 or the F2 generation compared to other genes. Nor do we find any evidence that the epigenetic reprogramming of ICRs in the germline is susceptible to nutritional restriction. However, we propose that those imprinted genes that are affected may play important roles in the foetal response to undernutrition and potentially its long-term sequelae. We suggest that recently described instances of dosage regulation by relaxation of imprinting are rare and likely to be highly regulated.
Summary Muscle stem cells (or muscle satellite cells [MuSCs]) are required for postnatal growth. Yet, the detailed characterization of myogenic progression and establishment of quiescence during this process remains poorly documented. Here, we provide an overview of myogenic cells heterogeneity and dynamic from birth to adulthood using flow cytometry. We demonstrated that PAX7+ cells acquire an increasing ability to progress in the myogenic program from birth to adulthood. We then simultaneously analyzed the cycling state (KI67 expression) of the MuSCs and progenitors (PAX7+) and their progression into myogenic precursors (PAX7−MYOD+) and differentiating cells (MYOG+) in vivo . We identified two distinct peaks of myogenic differentiation between P7–P10 and P21–P28, and showed that the quiescent MuSC pool is established between 7 and 8 weeks of age. Overall our study provides a comprehensive in vivo characterization of myogenic heterogeneity and demonstrates the highly dynamic nature of skeletal muscle postnatal growth process.
Muscle wasting is a major cause of morbidity in the elderly. Ku80 is required for DNA double strand repair and is implicated in telomere maintenance. Complete loss-of-function leads to reduced post-natal growth and severe progeria in mice. We examined the role of Ku80 in age-related skeletal muscle atrophy. While complete loss of Ku80 leads to pronounced aging in muscle as expected, accompanied by accumulation of DNA damage, loss of a single allele is sufficient to accelerate aging in skeletal muscle although post-natal growth is normal. Ku80 heterozygous muscle shows no DNA damage accumulation but undergoes premature telomere shortening that alters stem cell self-renewal through stress response pathways including p53. These data reveal an unexpected requirement for both Ku80 alleles for optimal progenitor function and prevention of early onset aging in muscle, as well as providing a useful model for therapeutic approaches.
Evidence suggests that the HIV-1 envelope glycoproteins play a role in the central nervous system (CNS) complications of AIDS. Endothelin-1 (ET-1) has also been implicated in brain injury and the progression of the AIDS dementia complex (ADC). Here, we used a real-time reverse transcription polymerase chain reaction assay and an immunometric assay to show that in vitro model of the blood-brain barrier (BBB) consisting of a monolayer co-culture of astrocytes and human brain microvascular endothelial cells (A-HBMEC) increased its expression of ET-1 mRNA and secretion of ET-1 peptide when infected with HIV-1. The enhanced expression of ET-1 occurred independently of viral replication as it was also induced by the viral glycoprotein coat HIV-1g120SF. These results show that one mechanism by which HIV-1 might affect the CNS is by inducing release of ET-1 by the BBB.
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