The ubiquitin-proteasome proteolytic pathway in heart vs skeletal muscle: effects of acute diabetes.

The ubiquitin-proteasome system is thought to play a major role in normal muscle protein turnover and to contribute to diabetes-induced protein wasting in skeletal muscle. However, its importance in cardiac muscle is not clear. We measured heart muscle mRNA for ubiquitin and for the C2 and C8 proteasomal subunits, the amount of free ubiquitin and the proteasome chymotrypsin-like proteolytic activity in control and diabetic rats. Results were compared to those in skeletal muscle (rectus). Heart ubiquitin, C2 and C8 subunit mRNA and proteolytic activity were significantly greater than in skeletal muscle (P

The role of insulin and other hormones in the regulation of amino acid and protein metabolism in humans.

While realizing the difficulties with the various methods used to study hormonal control of protein metabolism, there appear to be clear effects of both rapid-acting and slower-acting hormones. Moreover, some of these hormones affect protein metabolism in a dose dependent manner. Insulin and IGF-I appear to have differing effects at lower doses, with insulin primarily inhibiting protein degradation and IGF-I stimulating protein synthesis. At higher doses, infusions of insulin and IGF-I both seem to inhibit protein degradation and stimulate protein synthesis. Epinephrine primarily inhibits protein degradation whereas growth hormone primarily increases protein synthesis. Infusion of amino acids themselves can also increase protein synthesis. Thyroid hormone excess increases protein synthesis and protein degradation, with the latter effect predominating. Sex steroids appear to increase protein synthesis. To date, most interventions studying the metabolic effects of these hormones on protein metabolism have involved varying the concentration of one hormone at a time. In the complex milieu of many pathologic states (e.g. sepsis, renal failure or even the transition from fasting to feeding) multiple hormones change simultaneously. How interactions among these factors determine the overall response of body and muscle protein remains to be defined.

The immunoregulatory effects of prolactin in mice are time of day dependent.

The effects of timed administration of PRL on immune activities were investigated in male BALB/c mice. Ten daily injections of PRL (1 mg/kg) were made 0/24, 4, 8, 12, 16, or 20 h after light onset (HALO). On day 11, spleen cells were harvested between 1-3 HALO and cocultured with gamma-irradiated C57BL/6 spleen cells for 5 days, and proliferative responses to alloantigen were assayed (mixed lymphocyte reaction). When given in vivo at 4-12 HALO, PRL strongly stimulated proliferation by more than 2-fold, whereas PRL injections when given at 24 HALO substantially inhibited proliferation and had no effect when given at 16-20 HALO. When endogenous PRL secretion was stimulated for 7 days with injections of domperidone or 5-hydroxytryptophan, the splenocyte response increased by 48% and 64%, respectively, when injections were given at 9-10 HALO, but did not increase when they were given at 23-0 HALO. Inhibition of endogenous PRL secretion for 7 days with bromocriptine (2.5 mg/kg.day) inhibited splenocyte responsiveness by 40% when injected at 9 HALO, but had no effect when administered at 0 HALO. Furthermore, such bromocriptine treatment inhibited T- and B-cell mitogenic responses to Concanavalin-A (by 48%) and lipopolysaccharide (38%) when administered at 10, but not 0, HALO. In a manner similar to mixed lymphocyte reaction responses, daily PRL injections for 10 days at 11 HALO stimulated (40%) the in vivo delayed-type hypersensitivity response to antigen (azobenzenearsonate), whereas injections at 0 HALO were nonstimulatory. Bromocriptine treatment (1.5 mg/kg.day) suppressed the delayed-type hypersensitivity response (43% less than the control value) when administered at 10-12 HALO, but had no effect when administered at light onset. Timed PRL injections for 28 days in adult mice increased (42%) the total thymic cell number when administered at 11 HALO, but had no effect when injected at 0 HALO. Together, these results show that immunocyte responsiveness to PRL is time of day dependent. Thus, these findings support an essential and heretofore unrecognized circadian role in PRL regulation of immunity.

Circadian neuroendocrine role in age-related changes in body fat stores and insulin sensitivity of the male Sprague-Dawley rat.

A role for circadian neuroendocrine rhythms in the age-related development of obesity and insulin resistance was investigated in the male Sprague-Dawley rat. The phases and amplitudes of the plasma rhythms of several metabolic hormones (i.e., corticosterone, prolactin, insulin, and triiodothyronine) differed in lean, insulin-sensitive (3-week-old rats), insulin-resistant (8-week-old rats) and obese, insulin-resistant (44-week-old rats) animals. Simulation of the daily rhythms of endogenous corticosterone and prolactin by daily injections of the hormones at times corresponding to the peak levels found in 3-week-old rats reversed age-related increases in insulin resistance and body fat in older (5-6-month-old) rats. Ten such daily injections of corticosterone and prolactin in 12-14-week-old rats produced long-term reductions in body fat stores (30%), plasma insulin concentration (40%), and insulin resistance (60%) (determined by a glucose tolerance test) measured 11-14 weeks after the treatment. Alterations in circadian neuroendocrine rhythms may account for age-related changes in carbohydrate and lipid metabolism in the male Sprague-Dawley rat, and resetting of these rhythms by appropriately timed daily injections of corticosterone and prolactin may help maintain metabolism characteristic of younger animals.