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

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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.