The overall control of protein synthesis and breakdown

There are some generalisations that can be made about the regulation of protein synthesis and breakdown (summarised in Fig. 6.19). Two hormones have a general anabolic role (stimulating net protein synthesis) in the body: insulin and growth hormone. In people with a deficiency of insulin (insulin-dependent diabetes mellitus; see Chapter 10) there is marked loss of protein from the body - the 'melting of flesh into urine'. Treatment with insulin restores body protein. Growth hormone acts through the insulin-like growth factors IGF-1 and IGF-2, and has an important role during development. In the adult this is not of major importance; adults whose pituitaries have been removed do not need growth hormone to be replaced to lead fairly normal lives. However, growth hormone is beneficial in stimulating protein anabolism in patients who have lost protein through severe illness.

Mixture of amino acids

Mixture of amino acids

Strongyloides Stercoralis Life Cycle

Fig. 6.18 Major pathways for amino acid flow between tissues. The pathways are discussed in the text, with the exception of serine release by the kidney. The precursor for this is probably glycine (released from peripheral tissues). In the liver, serine may be converted to D-2-phosphoglycerate (or pyruvate in some species) and thus enter the hepatic pool of gluconeogenic precursors. Based loosely on Felig (1975) and Christensen (1982): for discussion of serine metabolism see Snell (1986); Snell & Fell (1990).

Fig. 6.18 Major pathways for amino acid flow between tissues. The pathways are discussed in the text, with the exception of serine release by the kidney. The precursor for this is probably glycine (released from peripheral tissues). In the liver, serine may be converted to D-2-phosphoglycerate (or pyruvate in some species) and thus enter the hepatic pool of gluconeogenic precursors. Based loosely on Felig (1975) and Christensen (1982): for discussion of serine metabolism see Snell (1986); Snell & Fell (1990).

Protein Breakdown Muscle

Fig. 6.19 Overall control of protein synthesis and breakdown in muscle (and other tissues). Some of the stimuli here are tissue-specific (especially physical activity, testosterone and P-adrenergic stimulation); more details are given in the text. IGFs are the insulinlike growth factors (IGF-1 and -2), generated in the liver in response to growth hormone (GH). p-adrenergic represents activation of P-adrenergic receptors, either by noradrenaline released at sympathetic nerve terminals or by adrenaline in the plasma.

Fig. 6.19 Overall control of protein synthesis and breakdown in muscle (and other tissues). Some of the stimuli here are tissue-specific (especially physical activity, testosterone and P-adrenergic stimulation); more details are given in the text. IGFs are the insulinlike growth factors (IGF-1 and -2), generated in the liver in response to growth hormone (GH). p-adrenergic represents activation of P-adrenergic receptors, either by noradrenaline released at sympathetic nerve terminals or by adrenaline in the plasma.

The male sex hormone, testosterone (a steroid hormone produced in the testes), also has a role in promoting protein synthesis, particularly in muscle. This was first realised because of the difference in average muscle strength between men and women. It became clear that this was a function of testosterone. Since that time, synthetic steroids have been developed which have increased anabolic tendencies and less androgenic (masculinising) tendencies - these are the anabolic steroids.

In individual tissues, there are other specific controlling factors. In skeletal muscle, the level of physical activity is an obvious one. The various factors generally work in concert; the effects of exercise and anabolic steroids, for instance, are greater than either alone. Skeletal muscle protein mass is also regulated by adrenergic influences. It has long been known that if a muscle is denervated - has its nerve supply cut - then it wastes away (atrophies). It has been assumed that this is because it no longer contracts, and therefore there is no 'training stimulus' to growth - so-called disuse atrophy. Now it appears that loss of an adrenergic stimulus may also be important. Administration of adrenergic P-stimulating drugs can increase muscle bulk. It is still not clear whether these act through one of the 'classical' P-adrenergic receptors or whether some new type of receptor is involved. One such agent is clenbuterol, which has been used in agriculture to increase muscle bulk in cows, and misused in the sports world.

Some endocrine glands are stimulated to growth by their own trophic (or tropic) (hormone-releasing) factors. A good example is the stimulation of the thyroid gland by thyroid-stimulating hormone (TSH) from the anterior pituitary. TSH increases thyroid size as well as stimulating thyroid hormone secretion (see Section 5.3.1). However, this is not of significance for the overall protein metabolism of the body.

The overall rate of protein breakdown to amino acids is also under hormonal control. Insulin itself may act more by restraining protein breakdown than by stimulating protein synthesis. Since there is continual turnover of protein, the net effect is the same. In addition, two hormones are regarded as having particularly catabolic effects: cortisol and the thyroid hormone triiodothyronine (T3).

The protein catabolic effect of cortisol does not affect all tissues equally. This is clearly seen in Cushing's syndrome, the disease caused by overproduction of cortisol from the adrenal cortex.2 In this condition there is loss of protein from both muscle and bone, and one of the consequences is a liability to bone fractures. The wasting of muscle is, however, somewhat selective and affects the so-called proximal muscles - those nearer the trunk rather than on the lower limbs. It also affects primarily the Type II, fast-twitch muscle fibres.

Loss of body mass, including muscle mass, is one of the features of thyroid excess, and it is clear that the thyroid hormones have a net degradative effect on muscle protein. In experimental models, T3 may also increase the rate of protein synthesis, but less than it increases protein degradation, so the net result is accelerated protein turnover and net loss of protein.

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