In skeletal muscle, excitation may cause loss of K+, increased extracellular K+ ([K+]o), intracellular Na+ ([Na+]i), and depolarization. Since these events interfere with excitability, the processes of excitation can be self-limiting. During work, therefore, the impending loss of excitability has to be counterbalanced by prompt restoration of Na+-K+ gradients. Since this is the major function of the Na+-K+ pumps, it is crucial that their activity and capacity are adequate. This is achieved in two ways: 1) by acute activation of the Na+-K+ pumps and 2) by long-term regulation of Na+-K+ pump content or capacity. 1) Depending on frequency of stimulation, excitation may activate up to all of the Na+-K+ pumps available within 10 s, causing up to 22-fold increase in Na+ efflux. Activation of the Na+-K+ pumps by hormones is slower and less pronounced. When muscles are inhibited by high [K+]o or low [Na+]o, acute hormone- or excitation-induced activation of the Na+-K+ pumps can restore excitability and contractile force in 10-20 min. Conversely, inhibition of the Na+-K+ pumps by ouabain leads to progressive loss of contractility and endurance. 2) Na+-K+ pump content is upregulated by training, thyroid hormones, insulin, glucocorticoids, and K+ overload. Downregulation is seen during immobilization, K+ deficiency, hypoxia, heart failure, hypothyroidism, starvation, diabetes, alcoholism, myotonic dystrophy, and McArdle disease. Reduced Na+-K+ pump content leads to loss of contractility and endurance, possibly contributing to the fatigue associated with several of these conditions. Increasing excitation-induced Na+ influx by augmenting the open-time or the content of Na+ channels reduces contractile endurance. Excitability and contractility depend on the ratio between passive Na+-K+ leaks and Na+-K+ pump activity, the passive leaks often playing a dominant role. The Na+-K+ pump is a central target for regulation of Na+-K+ distribution and excitability, essential for second-to-second ongoing maintenance of excitability during work.

Na+-K+ Pump Regulation and Skeletal Muscle Contractility

THYROXINE (T4), measured as protein-bound iodine, was the first hormone to be quantitated in human serum. As a consequence, it was possible to demonstrate clear relationships between circulating T4 concentrations and many of the physiological manifestations of thyroid hormone excess or deficiency. In 1952, 3,5,3′-triiodothyronine (T3) was identified in human plasma and metabolic studies in man soon led to the realization that this hormone was 3–4 times as potent metabolically as T4 (1–4). At that time, the question was first raised as to whether T4 or T3 was the “active” thyroid hormone (3). This question became even more pertinent when it was suggested first in 1955 (5) and shown conclusively in 1970 that T4 could be converted to T3 by peripheral human tissues (6, 7). These studies were made possible by the development of methods for quantitating T3 in human serum, initially by competitive protein binding techniques, followed soon thereafter by specific and sensitive RIAs.

Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications.

A large body of circumstantial evidence suggests that the basic unit of thyroid hormone action is the triiodothyronine nuclear receptor complex. This complex stimulates the formation, directly or indirectly, of a diversity of messenger RNA (mRNA) sequences. A generalized increase in mRNA as well as a disproportionate increase in a limited number of RNA sequences have been demonstrated. Regulation of thyroid hormone effects may be carried out largely at a local cellular level. Highly selective alterations in sensitivity to the triiodothyronine nuclear receptor complex may occur at specific target genes. Metabolic factors and hormones participate in such regulation. In a given tissue, alterations in the total number of receptor sites has not been shown to be useful as an index of thyroid hormone response, and local modulation of the response to the triiodothyronine receptor complex by a variety of factors other than triiodothyronine may be carried out at a postreceptor level.

Thyroid hormone action at the cellular level

Alterations in thyroid physiology and thyroid function tests occur in some patients with nonthyroidal illnesses. Low concentrations of serum triiodothyronine (T3) usually occur in nonthyroidal illnesses and are attributable largely to reduced extrathyroidal conversion of thyroxine (T4) to T3. Concentrations of serum total T4 may be low, normal, or high; alterations in serum binding of T4 explain the abnormality in most cases. Concentrations of serum reverse T3 are usually high because metabolic clearance is reduced. Whether patients with nonthyroidal illnesses with low T4 or T3, or both, are hypothyroid is uncertain; concentrations of free T4 have been estimated as low, normal, or high using different methods. Serum thyroid-stimulating hormone is typically normal. Low concentrations of T3 or T4, or both, in nonthyroidal illnesses may have a homeostatic significance. Low serum concentrations of T4 correlate with poor prognosis in nonthyroidal illnesses. Inhibitors of thyroid hormone binding and phagocytosis are present in normal tissues. Leakage of the inhibitors into the circulation may lower serum concentrations of T4 on one hand and compromise critical host defenses on the other.

Thyroid Function in Nonthyroidal Illnesses

Diet-induced alterations in thyroid hormone concentrations have been found in studies of long-term (7 mo) overfeeding in man (the Vermont Study). In these studies of weight gain in normal weight volunteers, increased calories were required to maintain weight after gain over and above that predicted from their increased size. This was associated with increased concentrations of triiodothyronine (T3). No change in the caloric requirement to maintain weight or concentrations of T3 was found after long-term (3 mo) fat overfeeding. In studies of short-term overfeeding (3 wk) the serum concentrations of T3 and its metabolic clearance were increased, resulting in a marked increase in the production rate of T3 irrespective of the composition of the diet overfed (carbohydrate 29.6 +/- 2.1 to 54.0 +/- 3.3, fat 28.2 +/- 3.7 to 49.1 +/- 3.4, and protein 31.2 +/- 2.1 to 53.2 +/- 3.7 microgram/d per 70 kg). Thyroxine production was unaltered by overfeeding (93.7 +/- 6.5 vs. 89.2 +/- 4.9 microgram/d per 70 kg). It is still speculative whether these dietary-induced alterations in thyroid hormone metabolism are responsible for the simultaneously increased expenditure of energy in these subjects and therefore might represent an important physiological adaptation in times of caloric affluence. During the weight-maintenance phases of the long-term overfeeding studies, concentrations of T3 were increased when carbohydrate was isocalorically substituted for fat in the diet. In short-term studies the peripheral concentrations of T3 and reverse T3 found during fasting were mimicked in direction, if not in degree, with equal or hypocaloric diets restricted in carbohydrate were fed. It is apparent from these studies that the caloric content as well as the composition of the diet, specifically, the carbohydrate content, can be important factors in regulating the peripheral metabolism of thyroid hormones.

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Dietary-induced alterations in thyroid hormone metabolism during overnutrition.

Fasting decreases the ratio of hepatic nuclear to serum triiodothyronine (T3) by diminishing the binding capacity of nuclear T3 receptors. In combination with the lower serum T3 concentration caused by fasting, the decrease in receptor content results in a marked decrease in nuclear T3-receptor complexes. The changes in T3 receptor content and circulating T3 in fasted animals appear to be independent synergistic adaptations for caloric conservation in the fasted state. Unlike changes in hormonal level, the modification of nuclear receptor content provides a mechanism that may protect cells with a low caloric reserve independently of the metabolic status of the whole animal.

http://science.sciencemag.org/content/sci/199/4329/686.full.pdf

George C. Schussler

Papers

Fasting decreases triiodothyronine receptor capacity