Understanding the effects of thin and thick filament proteins on the kinetics of Ca(2+) exchange with cardiac troponin C is essential to elucidating the Ca(2+)-dependent mechanisms controlling cardiac muscle contraction and relaxation. Unlike labeling of the endogenous Cys-84, labeling of cardiac troponin C at a novel engineered Cys-53 with 2-(4'-iodoacetamidoanilo)napthalene-6-sulfonic acid allowed us to accurately measure the rate of calcium dissociation from the regulatory domain of troponin C upon incorporation into the troponin complex. Neither tropomyosin nor actin alone affected the Ca(2+) binding properties of the troponin complex. However, addition of actin-tropomyosin to the troponin complex decreased the Ca(2+) sensitivity ( approximately 7.4-fold) and accelerated the rate of Ca(2+) dissociation from the regulatory domain of troponin C ( approximately 2.5-fold). Subsequent addition of myosin S1 to the reconstituted thin filaments (actin-tropomyosin-troponin) increased the Ca(2+) sensitivity ( approximately 6.2-fold) and decreased the rate of Ca(2+) dissociation from the regulatory domain of troponin C ( approximately 8.1-fold), which was completely reversed by ATP. Consistent with physiological data, replacement of cardiac troponin I with slow skeletal troponin I led to higher Ca(2+) sensitivities and slower Ca(2+) dissociation rates from troponin C in all the systems studied. Thus, both thin and thick filament proteins influence the ability of cardiac troponin C to sense and respond to Ca(2+). These results imply that both cross-bridge kinetics and Ca(2+) dissociation from troponin C work together to modulate the rate of cardiac muscle relaxation.
Objective We present three cases of thyroid dysfunction such as Hashimoto thyroiditis, Graves’ disease and subacute thyroiditis which developed few weeks after resolution of acute phase of COVID -19 infection in patients with no prior thyroid disease. Methods We discuss clinical presentation, diagnostic evaluation and subsequent management and follow-up in three patients. Results All three patients tested positive for COVID-19 infection prior to diagnosis. Patient 1. A 38-year-old female developed hypothyroidism 6 weeks after COVID-19 infection, confirmed by TSH 136 mIU/L (range 0.34–5.6), free T4 level 0.2 ng/dL (range 0.93–1.7). Patient 2. A 33-year-old female developed Graves’ disease 8 weeks after COVID-19 infection, with a TSH <0.01 mIU/L (range 0.4–4.5), Free T4 2.1 ng/dl (range 0.8–1.8), total T3 216 ng/dl (range 76–181), elevated TSI 309 (normal <140). A 24-h thyroid uptake was calculated at 47.1% (normal values between 8% and 35). Patient responded favorably to methimazole 10 mg in few weeks. Patient 3. A 41-year old healthy female developed thyroiditis at 6 weeks after COVID-19 infection, with a TSH 0.01 mIU/L and free T4 1.9 ng/dL accompanied by low 24-h thyroid uptake, calculated at 0.09%. Three weeks later, she developed hypothyroidism, with a TSH 67.04 mIU/L and free T4 0.4 ng/dl. Conclusion The temporal relationship between COVID-19 infection in the patients described here raises the question of possible effects of COVID-19 on the immune system and the thyroid gland.
Norman C, Rall JA, Tikunova SB, Davis JP. Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities. Am J Physiol Heart Circ Physiol 293: H2580-H2587, 2007. First published August 10, 2007; doi:10.1152/ajpheart.00039.2007.-We investigated whether changing thin filament Ca 2ϩ sensitivity alters the rate of contraction, either during normal cross-bridge cycling or when cross-bridge cycling is increased by inorganic phosphate (P i). We increased or decreased Ca 2ϩ sensitivity of force production by incorporating into rat skinned cardiac trabeculae the troponin C (TnC) mutants V44QTnCF27W and F20QTnCF27W . The rate of isometric contraction was assessed as the rate of force redevelopment (ktr) after a rapid release and restretch to the original length of the muscle. Both in the absence of added Pi and in the presence of 2.5 mM added Pi F27W . This study suggests that TnC Ca 2ϩ binding properties modulate the rate of cardiac muscle contraction at submaximal levels of Ca 2ϩ activation. This result has physiological relevance considering that, on a beat-to-beat basis, the heart contracts at submaximal Ca 2ϩ activation.force; thin filament CARDIAC MUSCLE CONTRACTION is initiated by Ca 2ϩ binding to troponin C (TnC), which triggers conformational changes on the thin filament, exposing myosin-binding sites on actin. After the myosin heads (cross bridges) attach to actin, the thin filaments slide along the thick filaments and the muscle contracts (18). The kinetics of cross-bridge cycling can be studied with several approaches. One approach has been developed by Brenner (3, 4). According to this protocol, a rapid shorteningrestretch maneuver mechanically detaches the cross bridges, and the rate at which the cross bridges reattach and generate force is a measure of the rate of contraction, known as the rate of force (tension) redevelopment (k tr ).In both cardiac and skeletal muscle, it is well established that k tr becomes faster with increasing levels of activation by Ca 2ϩ (5,6,13,28,46). Many studies have investigated the role Ca 2ϩ plays in the activation dependence of k tr (for review, see Ref. 13). It has been proposed that the effects of Ca 2ϩ on k tr occur either as a direct effect of Ca 2ϩ on the cross bridges or indirectly by activation of the thin filament, which subsequently allows cross bridges to cycle from non-force-generating states to force-generating states. Studies in skeletal muscle investigated the hypothesis that Ca 2ϩ has a direct effect on the cross bridge cycle. Caged inorganic phosphate (P i ) experiments suggest that Ca 2ϩ does not regulate the kinetics of P i release but rather the distribution of cross bridges between non-force-generating and force-generating states (25,45). Similarly, in vitro motility assays have shown that Ca 2ϩ , through binding to TnC, controls the number of cross bridges interacting with actin rather than directly controlling the rate of ATP hydrolysis or the filament sliding speed (14, 17). Moreover, Ca 2ϩ does...
We have studied growth hormone production in a patient with a bronchial carcinoid and acromegaly. The absence of growth hormone from the carcinoid tumour was demonstrated by extraction, cell culture and immunoperosidase techniques. Using a linked perfusion culture system, effluent from the bronchial carcinoid tumour culture stimulated a rapid release of growth hormone from a rat pituitary monolayer. This is the first time evidence of growth hormone releasing activity by a bronchial carcinoid has been demonstrated in a production.
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