How Pagonists Work

p-agonists specifically enhance the growth of muscle and give a small reduction in the growth of fat. p-agonists' effects are mediated by modifying specific metabolic signals in muscle and fat cells with a resulting increase in nutrients directed toward lean growth. Directing nutrients to tissues of highest priority is a normal metabolic process. This nutritive flow takes place as an ongoing hourly, daily, and weekly adjustment directed by internal body signals. In young growing pigs, more energy is directed toward lean than fat; however, in more mature, heavier pigs, a larger proportion of energy is directed toward fat. p-agonists modify the metabolic signals within muscle and fat cells to direct more nutrients to lean growth (Fig. 2).

The binding of p-agonists with specific receptors on the surface of muscle and fat cells (p-adrenergic receptors) generates these signals. When p-agonists bind

L644.969 ((32)

Zilpaterol ((32)

Fig. 1 Structure of several phenethanolamines evaluated as leanness enhancers in livestock. Current classifications of receptor subtype selectivity (b1 or b2 adrenergic receptor) are indicated.

to these receptors on the surface of the fat cell, biochemical signals are produced inside the cell that decrease fat synthesis and increase fat degradation, resulting in a slower rate of fat deposition. In muscle cells, the outcome of the internal signaling is a substantial increase in the rate of muscle protein synthesis and deposition. As a result, muscle synthesis is faster and fat synthesis is slower. Because it takes only half the energy to deposit lean compared to fat, the outcome is a leaner animal that utilizes feed more efficiently. Because this effect is primarily on muscle in the carcass, dressing percentage is increased.

A more detailed description of the proposed mechanism by which b-agonists affect muscle and fat cell synthesis through interaction with b-adrenergic receptors on the surface of muscle and fat cells is shown in Fig. 3. Activation of b-adrenergic receptors is coupled to Gs proteins and activation of adenyl cyclase (AC), which converts adenosine triphosphate (ATP) to cyclic adeno-sine monophosphate (cAMP), an intracellular signaling

Table 1 Factors that influence response to treatment with b agonists

Factor

Requirement

Compounds studied

Species studied

Dietary protein

Greater response with higher dietary protein

Clenbuterol

Pigs, broilers, rats

BRL47672

Ractopamine

Duration of treatment

Greater response during final finishing phase

Cimaterol

Pigs, cattle, sheep

Clenbuterol

l 644969

Ractopamine

Dosage

Differential effect on growth and leanness

Ractopamine

Pigs

Age or weight

Greater response with older, heavier animals

Cimaterol

Pigs, cattle

Ractopamine

Genetics

Effective in both fat and lean genetics

Cimaterol

Pigs, mice

Ractopamine

Without Beta-agonist

Nutrient Pool

With Beta-agonist

Nutrient Pool

Fig. 2 b agonists modify the metabolic signals in muscle and fat cell to enhance the rate of lean (muscle) growth.

molecule. The cAMP binds to the regulatory subunit of protein kinase A (PKA) to release its catalytic subunit. Regulation of intracellular enzymes is then accomplished through phosphorylation by protein kinase A. Activation of p-adrenergic receptors and the cAMP signaling pathway by p-agonists results in the activation of rate-limiting enzymes in lipolysis and inactivation of lipogenic enzymes involved in de novo synthesis of fatty acids and triglycerides.[7]

The effects of p-agonists on muscle result in muscle cell hypertrophy (Table 2) and increased lean mass. This effect is generally attributed to activation of the p-adrenergic receptor pathway. The outcome of the intracellular signaling in muscle is an increase in the abundance of total RNA and mRNA for myofibrillar

Beta Adrenergic Agonists

Table 2 Effect of p agonists

on myofiber diameter in

swine

Paylean treatment (ppm)

0

20

Number of animals

23

22

Red, m2

2,480

2,564

Intermediate, m2

1,783

2,216a

White, m2

3,467

4,048a

^Significantly different from control (P<0.05). (From Ref. [10].)

^Significantly different from control (P<0.05). (From Ref. [10].)

proteins, which is reflected in an increase in the fractional rate of protein synthesis in vivo. Results from these studies support the hypotheses that protein synthesis is substantially enhanced and that p-agonists do not affect protein degradation in muscle.[7]

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