97 research outputs found
The TWEAKâFn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice
The TNF-related cytokine TWEAK promotes skeletal muscle atrophy that is associated with classical disuse syndromes
Pharmacological characterization of a novel 5-hydroxybenzothiazolone-derived b2-adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies
Copyright ÂȘ 2019 by The Author(s) The anabolic effects of b2-adrenoceptor (b2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of b2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived b2-AR agonist in comparison with formoterol as a representative b2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human b2-AR and selectivity over the b1-AR and b3-AR. 5-HOB also shows potent agonistic activity at the b2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissueâderived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional b2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects
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The Myostatin gene: an overview of mechanisms of action and its relevance to livestock animals
Myostatin, also known as Growth Differentiation Factor 8, a member of the Transforming Growth Factor-beta (TGF-ÎČ) super-family is a negative regulator of muscle development. Myostatin acts at key points during pre- and post-natal life of amniotes which ultimately determine the overall muscle mass of an animal. Mutations have already demonstrated the impact of attenuating Myostatin activity on muscle development. A number of large animals including cattle, sheep, dogs and humans display the âdouble muscledâ phenotype due to mutations in the Myostatin gene. Here we firstly give an overview of the molecular pathways regulated by Myostatin that control muscle development. Then we describe the natural mutations and their associated phenotypes as well as the physiological influence of altering Myostatin expression in livestock animals (cattle, sheep, goat, horse, pig, rabbit and chicken). Knowledge of null alleles and polymorphisms in the Myostatin gene are of great interest in the animal breeding field and it could be utilized to improve meat production in livestock animals
Eculizumab treatment: stochastic occurrence of C3 binding to individual PNH erythrocytes
C5 blockade by eculizumab prevents complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). However, C3-bound PNH red blood cells (RBCs), arising in almost all treated patients, may undergo extravascular hemolysis reducing clinical benefits. Despite the uniform deficiency of CD55 and of CD59, there are always two distinct populations of PNH RBCs, with (C3+) and without (C3-) C3 binding
The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.
Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51âą) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism
Genomic Profiling Reveals That Transient Adipogenic Activation Is a Hallmark of Mouse Models of Skeletal Muscle Regeneration
<div><p>The marbling of skeletal muscle by ectopic adipose tissue is a hallmark of many muscle diseases, including sarcopenia and muscular dystrophies, and generally associates with impaired muscle regeneration. Although the etiology and the molecular mechanisms of ectopic adipogenesis are poorly understood, fatty regeneration can be modeled in mice using glycerol-induced muscle damage. Using comprehensive molecular and histological profiling, we compared glycerol-induced fatty regeneration to the classical cardiotoxin (CTX)-induced regeneration model previously believed to lack an adipogenic response in muscle. Surprisingly, ectopic adipogenesis was detected in both models, but was stronger and more persistent in response to glycerol. Importantly, extensive differential transcriptomic profiling demonstrated that glycerol induces a stronger inflammatory response and promotes adipogenic regulatory networks while reducing fatty acid ÎČ-oxidation. Altogether, these results provide a comprehensive mapping of gene expression changes during the time course of two muscle regeneration models, and strongly suggest that adipogenic commitment is a hallmark of muscle regeneration, which can lead to ectopic adipocyte accumulation in response to specific physio-pathological challenges.</p></div
Gene set enrichment mapping of glycerol- <i>vs.</i> CTX-injected muscle.
<p>Gene set enrichment analysis was performed on glycerol-injected compared to CTX-injected muscles 3 and 7 days after injection, and clustered according to gene set ontology. The size of nodes is proportional to the number of genes contained in the gene set. Red nodes: gene sets upregulated in glycerol <i>vs</i>. CTX model, blue nodes: gene sest downregulated in glycerol <i>vs</i>. CTX model, green bar: link between two gene sets sharing regulated genes.</p
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