143 research outputs found
PGC1β activates an antiangiogenic program to repress neoangiogenesis in muscle ischemia
Revascularization of ischemic skeletalmuscle is governed by a balance between pro- and antiangiogenic factors in multiple cell types but particularly in myocytes and endothelial cells. Whereas the regulators of proangiogenic factors are well defined (e.g.,hypoxia-inducible factor [HIF]), the transcriptional pathways encoding antiangiogenic factors remain unknown. We report that the transcriptional cofactor PGC1β drives an antiangiogenic gene program in muscle and endothelial cells. PGC1β transcriptionally represses proangiogenic genes (e.g., Vegfc, Vegfd, Pdgfb, Angpt1, Angpt2, Fgf1, and Fgf2) and induces antiangiogenic genes (e.g., Thbs1, Thbs2, Angstat, Pedf, and Vash1). Consequently, musclespecific PGC1β overexpression impairs muscle revascularization in ischemia and PGC1β deletion enhances it. PGC1β overexpression or deletion in endothelial cells also blocks or stimulates angiogenesis, respectively. PGC1β stimulates the antiangiogenic genes partly by coactivating COUP-TFI. Furthermore, roangiogenic stimuli such as hypoxia, hypoxia-mimetic agents, and ischemia decrease PGC1β expression in a HIF-dependent manner. PGC1β is an antiangiogenic transcriptional switch that could be targeted for therapeutic angiogenesis
Platelet biology in regenerative medicine of skeletal muscle
Platelet‐based applications such as platelet‐rich plasma (PRP) and platelet releasate have gained unprecedented attention in regenerative medicine across a variety of tissues as of late. The rationale behind utilizing PRP originates in the delivery of key cytokines and growth factors from α‐granules to the targeted area, which in turn act as cell cycle regulators and promote the healing process across a variety of tissues. The aim of the present review is to assimilate current experimental evidence on the role of platelets as biomaterials in tissue regeneration, particularly in skeletal muscle, by integrating findings from human, animal and cell studies. This review is composed of 3 parts: firstly, we review key aspects of platelet biology that precede the preparation and use of platelet‐related applications for tissue regeneration. Secondly, we critically discuss relevant evidence on platelet‐mediated regeneration in skeletal muscle focusing on findings from (i) clinical trials, (ii) experimental animal studies and (iii) cell culture studies; and thirdly, we discuss the application of platelets in the regeneration of several other tissues including tendon, bone, liver, vessels and nerve. Finally, we review key technical variations in platelet preparation that may account for the large discrepancy in outcomes from different studies. This review provides an up‐to‐date reference tool for biomedical and clinical scientists involved in platelet‐mediated tissue regenerative applications
Double rupture of interventricular septum and free wall of the left ventricle, as a mechanical complication of acute myocardial infarction: a case report
<p>Abstract</p> <p>Introduction</p> <p>Cardiac ruptures following acute myocardial infarction include rupture of the left ventricle free-wall, ventricular septal defects, and papillary muscle rupture. Double myocardial rupture is a rare complication of acute myocardial infarction (0.3 %) and the report of such cases is exclusively limited to a small series of autopsy studies.</p> <p>Case presentation</p> <p>In this report we present the unusual case of a 70-year-old woman with acute anteroseptal myocardial infarction, which was complicated by a combined rupture of the interventricular septum near the apex, and the free wall of the left ventricle with concomitant formation of a pseudoaneurysm. The double myocardial rupture was accidentally discovered 10 days later with echocardiography, when the patient, complaining only of mild exertional dyspnea, was hospitalized for a scheduled coronary angiography. The patient underwent successful surgical correction of the double myocardial rupture along with by-pass grafting.</p> <p>Conclusion</p> <p>This report highlights the importance of comprehensive noninvasive predischarge diagnostic evaluation of all postinfarct patients, since serious and potentially life-threatening complications might have not been suspected on clinical grounds.</p
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Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse
Background: Obese adults are prone to develop metabolic and cardiovascular diseases. Furthermore, over-weight expectant mothers give birth to large babies who also have increased likelihood of developing metabolic and cardiovascular diseases. Fundamental advancements to better understand the pathophysiology of obesity are critical in the development of anti-obesity therapies not only for this but also future generations. Skeletal muscle plays a major role in fat metabolism and much work has focused in promoting this activity in order to control the development of obesity. Research has evaluated myostatin inhibition as a strategy to prevent the development of obesity and concluded in some cases that it offers a protective mechanism against a high-fat diet.
Results: We hypothesised that myostatin inhibition should protect not only the mother but also its developing foetus from the detrimental effects of a high-fat diet. Unexpectedly, we found muscle development was attenuated in the foetus of myostatin null mice raised on a high-fat diet. We therefore re-examined the effect of the high-fat diet on adults and found myostatin null mice were more susceptible to diet-induced obesity through a mechanism involving impairment of inter-organ fat utilization.
Conclusions: Loss of myostatin alters fatty acid uptake and oxidation in skeletal muscle and liver. We show that abnormally high metabolic activity of fat in myostatin null mice is decreased by a high-fat diet resulting in excessive adipose deposition and lipotoxicity. Collectively, our genetic loss-of-function studies offer an explanation of the lean phenotype displayed by a host of animals lacking myostatin signalling.
Keywords: Muscle, Obesity, High-fat diet, Metabolism, Myostati
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Platelet releasate promotes skeletal myogenesis by increasing muscle stem cell commitment to differentiation and accelerates muscle regeneration following acute injury
Aim: The use of platelets as biomaterials has gained intense research interest. However,
the mechanisms regarding platelet-mediated skeletal myogenesis remain to be established.
The aim of this study was to determine the role of platelet releasate in skeletal myogenesis
and muscle stem cell fate in vitro and ex vivo respectively.
Methods: We analysed the effect of platelet releasate on proliferation and differentiation of
C2C12 myoblasts by means of cell proliferation assays, immunohistochemistry, gene
expression and cell bioenergetics. We expanded in vitro findings on single muscle fibres by
determining the effect of platelet releasate on murine skeletal muscle stem cells using
protein expression profiles for key myogenic regulatory factors.
Results: TRAP6 and collagen used for releasate preparation had a more pronounced effect
on myoblast proliferation versus thrombin and sonicated platelets (P<0.05). In addition,
platelet concentration positively correlated with myoblast proliferation. Platelet releasate
increased myoblast and muscle stem cell proliferation in a dose-dependent manner, which
was mitigated by VEGFR and PDGFR inhibition. Inhibition of VEGFR and PDGFR ablated
MyoD expression on proliferating muscle stem cells, compromising their commitment to
differentiation in muscle fibres (P<0.001). Platelet releasate was detrimental for myoblast
fusion and affected differentiation of myoblasts in a temporal manner. Most importantly we
show that platelet releasate promotes skeletal myogenesis through the PDGF/VEGF-Cyclin
D1-MyoD-Scrib-Myogenin axis and accelerates skeletal muscle regeneration after acute
injury.
Conclusion: This study provides novel mechanistic insights on the role of platelet releasate
in skeletal myogenesis and set the physiological basis for exploiting platelets as biomaterials
in regenerative medicine
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Attenuation of oxidative stress-induced lesions in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis through the inhibition of Nox2 activity
Obesity leading to hyperlipidaemia and atherosclerosis is recognised to induce
morphological and metabolic changes in many tissues. However, both hyperlipidaemia and
atherosclerosis can occur in the absence of obesity. The impact of the latter scenario on
skeletal muscle and liver is not understood sufficiently. In this regard, we used the
Apolipoprotein E-deficient (ApoE-/-) mouse model, an established model of hyperlipidaemia
and atherosclerosis, that does not become obese when subjected to a high-fat diet, to
determine the impact of Western-type diet (WD) and ApoE deficiency on skeletal muscle
morphological, metabolic and biochemical properties. To establish the potential of
therapeutic targets, we further examined the impact of Nox2 pharmacological inhibition on
skeletal muscle redox biology. We found ectopic lipid accumulation in skeletal muscle and
the liver, and altered skeletal muscle morphology and intramuscular triacylglycerol fatty acid
composition. WD and ApoE deficiency had a detrimental impact in muscle metabolome,
followed by perturbed gene expression for fatty acid uptake and oxidation. Importantly, there
was enhanced oxidative stress in the skeletal muscle and development of liver steatosis,
inflammation and oxidative protein modifications. Pharmacological inhibition of Nox2
decreased reactive oxygen species production and protein oxidative modifications in the
muscle of ApoE-/- mice subjected to a Western-type diet. This study provides key evidence to
better understand the pathophysiology of skeletal muscle in the context of hyperlipidaemia
and atherosclerosis and identifies Nox2 as a potential target for attenuating oxidative stress
in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia
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Symmorphosis through dietary regulation: a combinatorial role for proteolysis, autophagy and protein synthesis in normalising muscle metabolism and function of hypertrophic mice after acute starvation
Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production
Prenatal muscle development in a mouse model for the secondary dystroglycanopathies
The defective glycosylation of α-dystroglycan is associated with a group of muscular dystrophies that are collectively referred to as the secondary dystroglycanopathies. Mutations in the gene encoding fukutin-related protein (FKRP) are one of the most common causes of secondary dystroglycanopathy in the UK and are associated with a wide spectrum of disease. Whilst central nervous system involvement has a prenatal onset, no studies have addressed prenatal muscle development in any of the mouse models for this group of diseases. In view of the pivotal role of α-dystroglycan in early basement membrane formation, we sought to determine if the muscle formation was altered in a mouse model of FKRP-related dystrophy
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A roadmap towards a circular and sustainable bioeconomy through waste valorization
Municipal solid waste and food supply chain waste are globally generated in large quantities from various sectors including various stages of food supply chains, municipalities, open markets and catering services. A prevailing priority in the EU is to stimulate the transition towards a circular economy that fosters the promotion of sustainable and resource-efficient policies for long-term socio-economic and environmental benefits. Common practices for waste management include landfill disposal, anaerobic digestion, composting and wastewater treatment. Recently, new technologies have been introduced to produce value-added products from agricultural residues and food processing side streams. Integrated and holistic approaches for organic waste utilization as industrial feedstocks will boost the transition towards the bio-economy era. The establishment of circular economy would expand and diversify the market outlets of bio-based products. This review provides an overview of the current methods on waste and by-product streams bioconversion to develop biorefinery concepts
Investigating A Dose Response Relationship between High Fat Diet Consumption and the Contractile Performance of Isolated Mouse Soleus, EDL and Diaphragm Muscles
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