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Carmen, S.

Publications and source records attributed to Carmen, S..

2 recordsLinked to original sources

Transcriptomic Analysis Reveals MSTN Mutations and Mechanisms of Muscle Hypertrophy in a New Guinea Pig Breed

The guinea pig (Cavia porcellus), a species native to Peru, is valued for its meat production, where muscle development is essential for productive efficiency. The new Kuri breed, obtained through selective breeding and genetic selection, has shown a phenotype with more developed musculature compared to native guinea pigs. In this study, we conducted a comparative transcriptomic analysis between Native and Kuri breed guinea pig, complemented by histological analysis of the semitendinosus muscle to investigate the underlying mechanisms responsible for the differences in muscle morphology. Histological analysis revealed a significant increase in muscle fiber area in the Kuri breed compared to the native guinea pigs. At the molecular level, key mutations were identified in the MSTN gene, including variants in the 3 UTR region and a frameshift mutation, which alter the genes inhibitory function on muscle growth. Additionally, differences were observed in the expression of pathways related to muscle degradation, energy metabolism, and angiogenesis, which explain the greater muscle hypertrophy in the Kuri breed. These findings provide a first understanding of the genetic mechanisms responsible for muscle hypertrophy in the Kuri breed and suggest candidate genes for improving meat quality through molecular genetic breeding programs in guinea pigs. AUTHOR SUMMARYThe guinea pig in Peru is valued for its meat production. The new Kuri breed, obtained through selective breeding and genetic selection has shown a phenotype with more developed musculature compared to other breeders. In our study, comparative transcriptomic analysis between Native and Kuri breed guinea pig, complemented by histological analysis of the semitendinosus muscle to investigate the underlying mechanisms responsible for the differences in muscle morphology. Histological analysis showed significant increase in muscle fiber area in the Kuri breed compared to the native. Furthermore, it is the first time that we identify in guinea pig, key mutations in the MSTN gene, which alter the genes inhibitory function on muscle growth. The impact of this finding will allow us to plan genetic improvement strategies in this species that promote muscle hypertrophy, paving the way for future research and its potential impact on guinea pig production.

molecular biology↗

Tozorakimab (MEDI3506): a dual-pharmacology anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products - epidermal growth factor receptor (RAGE-EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M-1 s-1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 x 107 M-1 s-1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

immunology↗