Alteration of collagen synthesis and cross-link profile by beta-adrenergic agonists

β-肾上腺素能激动剂改变胶原合成和交联特征

• 批准号: RGPIN-2014-06641
• 负责人: Bruce, Heather
• 金额: $ 2.19万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=646407
• 关键词: Alteration; collagen; synthesis; cross; link

The use of beta-adrenergic agonists (ß-AA) such as clenbuterol as bronchial dilators in human medicine to control the symptoms of asthma and chronic pulmonary obstructive disease is widespread. Long-term (greater than or equal to one day) use is associated with increased accumulation of collagen in muscle cells, and can lead to both cardiac and skeletal muscle tissue diseases. This is a concern not only to human medicine but to animal agriculture as well because the ß-AA ractopamine hydrochloride (RAC) and zilpaterol hydrochloride (ZIL) are approved for use in Canada as growth promotants and re-partitioning agents to increase lean meat yield and feed efficiency in cattle. That RAC and ZIL have the potential to affect intramuscular collagen suggests that they may also affect meat eating quality because the quantity of collagen and the density of its mature, heat-stable crosslinks have been linked to increased toughness. Recent research by the applicant indicated that supplementation of cattle diets with RAC did not increase the total collagen in the muscles of cattle, but did decrease the density of the heat-stable collagen crosslink pyridinoline (PYR) on a molar (0.23 and 0.17 mole PYR/mole collagen, control versus RAC, P < 0.001) and per gram raw muscle (2.86 versus 2.60 nmol PYR/g raw muscle, control versus RAC, P < 0.05) basis. Further research by the applicant and her team showed that the implantation of beef cattle with estrogen-progesterone hormone growth promotants (HGP) also did not change total collagen concentration in the gluteus medius muscle (GM, top sirloin), but it did increase the concentration of another mature collagen crosslink Ehrlich's Chromogen (EC) on a molar (0.38 to 0.43 mol EC/mol collagen, control versus treated, P < 0.05) and per gram raw muscle basis (4.34 to 4.78 nmol/g raw muscle, control versus treated, P < 0.05). Additionally, there was a trend for the concentration of PYR to increase with HGP use from 0.18 (control) to 0.21 mol PYR/mol collagen (P < 0.1). These results suggested that the contribution of collagen to cooked beef toughness may decrease with ß-AA administration but increase with the use of steroidal growth promotants. The use of commercially available growth promoting substances in the beef industry is widespread and although their effects on body weight gain, feed efficiency and carcass composition are well known, their impact on intramuscular collagen is not. These results are the first to indicate that administration of ß-AA and HGP can affect the density of intramuscular mature collagen crosslinks and change the contribution of collagen to cooked beef toughness. That HGP and ß-AA produced different structural modifications in skeletal muscle collagen indicated that the mechanisms of collagen synthesis and turnover in response to these growth promotants were markedly different; consequently, the short term objectives of the proposed research are to elucidate the biochemical pathways by which ß-AA and HGP affect collagen crosslinking. These objectives are the next logical steps in a long term research program devoted to investigating the mechanisms controlling the synthesis and crosslinking of collagen and its impact on meat quality. This research is fundamental to fully understand the control mechanisms of collagen synthesis systemically and will have broad applications not only for animal production but for the prevention of tissue fibrosis during the treatment of human injury or disease and will contribute to the training of six highly qualified personnel.

β-肾上腺素能激动剂（β-AA）如克仑特罗在人类医学中作为支气管扩张剂以控制哮喘和慢性肺阻塞性疾病的症状是广泛使用的。 长期（大于或等于一天）使用与肌肉细胞中胶原蛋白积聚增加有关，并可能导致心脏和骨骼肌组织疾病。 这不仅是人类医学的关注点，而且也是畜牧业的关注点，因为在加拿大批准将A-AA盐酸莱克多巴胺（RAC）和盐酸齐帕特罗（ZIL）用作生长促进剂和再分配剂，以增加牛的瘦肉产量和饲料效率。 RAC和ZIL有可能影响肌内胶原蛋白，这表明它们也可能影响肉类食用质量，因为胶原蛋白的数量及其成熟的热稳定交联密度与韧性增加有关。 申请人最近的研究表明，用RAC补充牛饮食不会增加牛肌肉中的总胶原蛋白，但确实降低了摩尔胶原蛋白上的热稳定胶原蛋白交联吡啶啉（PYR）的密度。（0.23和0.17摩尔PYR/摩尔胶原，对照对RAC，P < 0.001）和每克生肌（2.86对2.60 nmol PYR/g生肌，对照对RAC，P < 0.05）基础。 申请人及其团队的进一步研究表明，用雌激素-孕酮激素生长促进剂（HGP）植入肉牛也没有改变臀中肌中的总胶原蛋白浓度（GM，顶级牛腩），但它确实增加了另一种成熟胶原交联埃利希色原（EC）在磨牙上的浓度（0.38至0.43 mol EC/mol胶原，对照组与处理组，P < 0.05）和每克生肌基础（4.34至4.78 nmol/g生肌，对照组与处理组，P < 0.05）。 此外，PYR的浓度有随着HGP的使用而增加的趋势，从0.18（对照）增加到0.21 mol PYR/mol胶原（P < 0.1）。 这些结果表明，胶原蛋白对煮熟的牛肉韧性的贡献可能会随着α-AA的施用而减少，但随着类固醇生长促进剂的使用而增加。 在牛肉工业中广泛使用市售的生长促进物质，尽管它们对体重增加、饲料效率和胴体组成的影响是众所周知的，但它们对肌内胶原蛋白的影响却不是。 这些结果首次表明，给予α-AA和HGP可以影响肌内成熟胶原交联的密度，并改变胶原对熟牛肉韧性的贡献。 HGP和HGP-AA在骨骼肌胶原中产生不同的结构修饰，这表明胶原合成和周转对这些生长促进剂的反应机制明显不同;因此，拟议研究的短期目标是阐明HGP-AA和HGP影响胶原交联的生化途径。这些目标是长期研究计划的下一个逻辑步骤，该计划致力于研究控制胶原蛋白合成和交联的机制及其对肉质的影响。 这项研究对于全面了解胶原蛋白合成的控制机制是至关重要的，不仅对动物生产，而且对预防人类损伤或疾病治疗期间的组织纤维化具有广泛的应用，并将有助于培养六名高素质的人员。