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

在人类医学中，使用β-肾上腺素能激动剂如克伦特罗作为支气管扩张剂来控制哮喘和慢性阻塞性肺疾病的症状是很普遍的。长期使用(大于或等于一天)会增加肌肉细胞中胶原的积累，并可能导致心肌和骨骼肌组织疾病。这不仅是人类医学关注的问题，也是动物农业关注的问题，因为在加拿大，莱克多巴胺盐酸盐(RAC)和盐酸齐帕特罗(ZIL)已被批准用作生长促进剂和再分配剂，以提高牛的瘦肉产量和饲料效率。RAC和ZIL有可能影响肌肉内的胶原蛋白，这表明它们也可能影响肉类的食用品质，因为胶原蛋白的数量及其成熟的、热稳定的交联物的密度与增韧有关。申请人最近的研究表明，添加RAC的牛日粮不会增加牛肌肉中的总胶原蛋白，但确实降低了耐热稳定的胶原蛋白(PYR)在摩尔(0.23和0.17摩尔PYR/摩尔胶原，对照组与RAC，P&lt；0.001)和每克生肌(2.86nmolPYR/g生肌，对照组与RAC，P&lt；0.05)的密度。申请人和她的团队的进一步研究表明，植入雌孕激素生长激素促进剂(HGP)的肉牛也没有改变臀中肌(GM，顶部牛腰肌)中的总胶原浓度，但它确实增加了另一种成熟的胶原交联物Ehrlich‘s Chromogen(EC)在磨牙上的浓度(对照组与处理组相比，0.38至0.43molEC/mol胶原，P&lt；0.05)，以及每克生肌(对照组与处理组，每克生肌4.34至4.78nmol/g肌肉，P&lt；0.05)的浓度。此外，随着HGP用量的增加，PYR的浓度有增加的趋势，从0.18(对照)增加到0.21molPYR/MOL胶原(P&lt；0.1)。这些结果表明，胶原蛋白对熟牛肉韧性的贡献可能会随着添加了β-AA而降低，但随着类固醇生长促进剂的使用而增加。商业上可获得的促生长物质在牛肉行业中的使用是广泛的，尽管它们对体重增加、饲料效率和屠体组成的影响是众所周知的，但它们对肌肉内胶原的影响还不是很清楚。这些结果首次表明，肌内成熟胶原蛋白交联物的密度和胶原蛋白对牛肉熟肉韧性的贡献都会受到不同剂量的β-AA和HGP影响。HGP和HGP对骨骼肌胶原产生不同的结构修饰，说明这两种促生长剂对胶原合成和转化的响应机制明显不同；因此，本研究的短期目标是阐明BGP和HGP影响胶原交联化的生化途径。这些目标是长期研究计划的下一个合乎逻辑的步骤，该计划致力于研究胶原蛋白的合成和交联的控制机制及其对肉类质量的影响。本研究为全面系统地了解胶原合成的调控机制奠定了基础，不仅在动物生产中有广泛的应用，而且在人类创伤或疾病治疗中预防组织纤维化方面也将有广泛的应用，并将有助于培养6名高素质的人才。

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.