Intact skin is composed of dermis and epidermis, which have different structure, function, and turnover/growth rates.12 The dermis serves as a base physically and nutritionally supporting the epidermis, whereas the epidermis exerts the barrier function of the skin. Hence, it is important to develop experimental methods not only to quantify protein synthesis in the whole skin, but also to differentiate the metabolic regulation of these two components of the skin, under various physiological and pathophysiological conditions. Using rabbit ear as a skin model, Zhang et al.5 found that the dermal protein contains 75.7% of the total cutaneous phenylalanine and 97.9% of the total cutaneous proline; the remaining 24.3% of phenylalanine and 2.1% of proline reside in the epidermal protein. Taking advantage of the different distribution of amino acids in these two proteins, the investigators were able to use stable isotope L-[ring-13C6]phenylalanine and [15N]proline tracers to estimate the in vivo rates of protein synthesis and breakdown distinctively in the dermis and epidermis layers of the skin tissue. Their results indicate that for rabbit skin, the synthesis rate of dermal skin was about 9 mg per 100 g wet weight per day with the same rate of protein breakdown, indicating that skin protein maintains its homeostasis in normal physiological conditions, including short periods of fasting. In addition, the synthesis and breakdown rate of epidermal protein was approximately ten times that found in the dermal protein. It is likely that such a quick turnover rate is of pivotal importance in the wound healing process after injury. Their studies also demonstrated a significant transport of amino acids from dermis to epidermis, supporting the notion that an intact dermis is essential in the overall process of wound repair.
Physiological Regulation of Wound Metabolism and Wound Healing Process in Relation to Whole Body Metabolic State
With the established metabolism models described above, it was then possible to assess the effect of whole body protein nutritional status and its relationship with the regional wound healing process.
Using this model, Zhang et al.16 reported that the synthesis of DNA and proteins in skin proceeded independently, because the fractional synthesis of whole skin DNA from the de novo nucleotide synthesis pathway was about 3.26 ± 0.593% per day, with DNA synthesis in dermis 3.08 ± 1.86% per day (P = 0.38); however, the fractional synthesis rates of whole skin protein were distinctively 5.35 ± 4.42% per day, which was greater (P < 0.05) than that of the dermal proteins at 2.91 ± 2.52% per day. The results indicate that cell division and protein synthesis are likely regulated by different mechanisms.
This animal model also allows for a simultaneous quantitative evaluation of protein metabolism in the skin and muscle tissues and their possible relationship in health and disease. It was found that in healthy animals, 64 h of fasting resulted in negative muscle protein balance. Nutritional support with an amino acid mixture and lipid significantly improved muscle protein balance, although it remained in a negative state. Amino acid and lipid feeding plus the use of insulin resulted in a positive protein balance in muscle. Despite the positive and negative responses seen in muscle, protein kinetics in skin protein maintained a balanced state under all these circumstances in healthy animals.6 The data further indicate that the stability of skin protein metabolism was maintained through a mechanism in the efficient reutilization, or recycling, of the amino acids released from protein breakdown for protein synthesis in the skin.6 Therefore, under healthy conditions, skin maintains the homeostasis of its protein mass in response to short-term changes in nutritional status and hormonal environment, in contrast to the responses seen in muscle protein metabolism. These findings are also supported by those of Cherel et al.,18 who reported that skin protein mass of healthy rats remained unchanged even after 5 d of fasting. Therefore, skeletal muscle is a mobilizable source of amino availability in the body, but skin is not. This in vivo skin metabolism model can further be applied to investigate the difference in the regulation of skin and muscle protein metabolism under various physiological and pathological conditions, including thermal injury and other critical illness.
After inducing a scar burn to the ear skin, the rates of both protein synthesis and breakdown in the wounded skin were increased, with the increment in proteolysis significantly exceeding protein synthesis, resulting in negative protein balance. Providing insulin combined with glucose and amino acids infusion to maintain a eug-lycemia and eu-amino acidemia,7,8 the investigators found that when the insulin was given at a dose similar to that used in the above-mentioned healthy animals,6 protein metabolism in the burned skin tissue changed from negative to positive balance, mainly due to the inhibition of proteolysis. The observed change in skin was in parallel to the improvement of skeletal muscle protein balance. It appears that after thermal injury, combined use of the anabolic agent insulin and a nutrient supply improved both skin and muscle protein metabolism; hence, improvement of whole body nutritional status is accompanied by positive skin protein balance. However, the investigators reported that short-term infusion of growth hormone did not result in improvement of protein metabolism in the skin or in the muscle.7 It is interesting to note that the anabolic effect of insulin on thermal-injured skin required a simultaneous supplementation of amino acids, providing either amino acids alone or insulin alone, but this did not have a positive effect on skin protein metabolism.8 These observations on the regulation of skin protein metabolism after burn injury seem to be similar to those seen in muscle tissues of healthy subjects. It was reported that the anabolic effects of insulin on whole body protein metabolism also required a simultaneous exogenous amino acid supplementation.1920
The effect of a specific nutrient on skin and whole body protein metabolism was also investigated on the same animal model. It was found that leucine-enriched amino acid feeding simultaneously improved protein metabolism in both muscle and skin.9
The application of the stable isotope tracer method and animal models allows for the in vivo investigation of the quantitative and dynamic changes in skin, muscle, and whole body protein metabolism. The above studies revealed the following:
1. In healthy conditions, the biochemistry of cell proliferation (DNA synthesis) and protein synthesis in the skin are differently regulated.
2. Protein synthesis rates in the epidermis are about ten times those in the dermis, indicating that a very active metabolic process for wound repair occurs in the epidermis component of the skin, and also stressing the importance of an intact dermis in transporting nutrients and in supporting epidermis protein synthesis.
3. In healthy animals, skin protein metabolism is maintained in a dynamically stable condition in response to short-term changes in nutritional status (starvation, amino acid and insulin) as compared to the immediate responses seen in muscle protein. However, prolonged malnutrition results in a reduced rate of collagen protein synthesis accompanied by poor protein nutrition states.
4. After thermal injury, the injured skin is in negative protein balance, in parallel with the net loss of protein from whole body and muscle tissues, and hence, a negative nitrogen balance is also found in skin tissue. Insulin combined with glucose and exogenous amino acid supply and leucine-enriched amino acid feeding improves both skin and muscle protein metabolism.
These findings provide direct evidence that in an injured condition, improvement of whole body protein nutritional status parallels protein anabolism in the wound protein. Hence, nutritional support is important in the wound healing process, and the modulation of anabolic factors and nutrients in the feeding formula would help promote not only whole body but also skin protein metabolism. A positive protein balance in the skin would accelerate the wound healing process.
The findings from animal models further support the following clinical practice and observations.
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