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Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy.

Mutations in cardiac Troponin T (TnT) are responsible for approximately 15% of all cases of familial hypertrophic cardiomyopathy (FHC). This review summarizes recent data from in vitro assays, transgenic models and clinical studies on how TnT mutations alter the regulation of cardiac muscle contraction. Each TnT mutation has somewhat different effects on myofilament properties (increased myofilament Ca(2)+ sensitivity, decreased maximal force, decreased binding affinity to the thin filament, impaired pH-regulation). But when the in vitro data are correlated with the results from the transgenic models, essentially all mutations can be predicted to result in: (1) impaired relaxation, (2) reduced diastolic compliance, (3) reduced contractile reserve, (4) preserved systolic function under baseline conditions, and (5) cardiac dysfunction under inotropic stimulation. Thus, the alterations of myofilament function caused by TnT mutations likely play an important role in the pathogenesis of FHC.

Animals↗

Motor neuron targeting of IGF-1 attenuates age-related external Ca2+-dependent skeletal muscle contraction in senescent mice.

A population of fast muscle fibers from aging mice is dependent on external Ca(2+) to maintain tetanic force during repeated contractions. We hypothesized that age-related denervation in muscle fibers plays a role in initiating this contractile deficit, and that prevention of denervation by IGF-1 overexpression would prevent external Ca(2+)-dependent contraction in aging mice. IGF-1 overexpression in skeletal muscle prevents age-related denervation, and prevented external Ca(2+)-dependent contraction in this work. To determine if the effects of IGF-1 overexpression are on muscle or nerve, aging mice were injected with a tetanus toxin fragment-C (TTC) fusion protein that targets IGF-1 to spinal cord motor neurons. This treatment prevented external Ca(2+)-dependent contraction. We also show evidence that injections of the IGF-1-TTC fusion protein prevent age-related alterations to the nerve terminals at the neuromuscular junctions. We conclude that the slow age-related denervation of fast muscle fibers underlies dependence on external Ca(2+) to maintain tetanic force in a population of muscle fibers from senescent mice.

Aging↗

Augmented tissue oxygen supply during striated muscle contraction in the hamster. Relative contributions of capillary recruitment, functional dilation, and reduced tissue PO2.

To investigate the relative contributions of alterations in blood flow, capillary density, and tissue PO2 to elevated oxygen delivery in working muscle, we conducted experiments on the suffused hamster cremaster muscle, using in vivo microscopic techniques. Muscle PO2 was measured during striated muscle twitch contraction at 1 Hz. Tissue oxygenation was changed by using suffusion solutions equilibrated with 0%, 5%, 10%, 21%, or 50% oxygen. Contraction caused an increase in capillary density (capillary recruitment), whose magnitude was related to the equilibration gas and, thus, to the suffusate PO2. Capillary recruitment first increased as the oxygen content was raised, peaked with 10% oxygen, and then diminished with higher oxygen content. Arteriolar functional dilation was also observed; when oxygen was raised above 21%, dilation was decreased. The data suggest that oxygen supply is increased primarily by arteriolar conductance changes with low suffusion solution oxygen (0% to 5%), and by capillary recruitment and increased PO2 gradients above 10% oxygen. When vasomotor tone was increased by addition of norepinephrine to the suffusion medium, the changes observed were similar to those observed when oxygen was increased. Therefore, we propose that the altered microvascular responses during vasoconstriction are a function of vascular tone rather than the levels of tissue PO2. A model is proposed which may partially explain the relations among vascular tone, functional dilation, and capillary recruitment. Our data also suggest that tissue PO2 may not be precisely regulated about a narrowly defined set point in this striated muscle but that, instead, tissue PO2 is a dependent variable controlled by the integrated effects of capillary recruitment, functional vasodilation, and altered metabolism.

Animals↗

Partition between volitional and induced forces in electrically augmented dynamic isometric muscle contractions.

Augmentation of force in partially deficient muscles can be achieved by combining electrical stimulation (ES) with their volitional activation (hybrid activation). However, while the overall torque results from the combination of the volitional and the electrically-induced torque components, the exact share between these components is not known. In a previous work, we described a method to resolve the share between the torque components under isometric static contractions. In this work, we extend our analysis to the case of isometric dynamic contractions. Five healthy subjects were instructed to contract their Tibialis Anterior (TA) muscles according to a typical gait-like dynamic torque pattern, that was visually displayed to them, while monitoring their actual ankle torque and TA electromyography (EMG). These experiments were done with and without augmented activation by means of ES. A computational algorithm was developed to dissociate the volitional from the overall torque, based on EMG signal processing and on precalibration of the dynamic system of the volitional torque versus EMG. The results indicated the quantitative relations between decrease in the volitional torque and the required increase in ES enhancement. The developed method also demonstrated what ES intensity profile is necessary to produce a desired overall torque output. This provides the means for designing an adaptive rehabilitation device for the hybrid activation of deficient muscles.

Adult↗

Effect of leg muscle contraction velocity on functional performance in older men and women.

OBJECTIVES: To explore the relationship between impairment (skeletal muscle strength and contraction velocity) and function in community-dwelling older adults. DESIGN: Cross-sectional. SETTING: University-based human physiology laboratory. PARTICIPANTS: One hundred one men and women (aged 75-90). MEASUREMENTS: Muscle strength and contraction velocity during bilateral leg press (LP) were calculated during one-repetition maximum (1RM) and 40% 1RM. A short physical performance battery (SPPB) and gait speed (GS) from a 400-m self-paced walk assessed function. Sex differences in LP strength and contraction velocity (at 40% 1RM) were assessed. The relationship between these variables and function was also examined. RESULTS: Lower extremity strength and contraction velocity were significantly associated with GS (P=.02 and P=.005, respectively) and SPPB (P<.001 and P=.009, respectively) in men only. Contraction velocity, but not muscle strength, was significantly associated with GS (P<.001) and SPPB (P=.02) in women. CONCLUSION: Sex differences exist in the relationship between impairment (muscle strength and contraction velocity) and function. Older men and women may employ different strategies to achieve success on different functional tasks. These findings may have important implications for clinicians practicing geriatric rehabilitation.

Aged↗

Regulation of urinary bladder smooth muscle contractions by ryanodine receptors and BK and SK channels.

This study examines the roles of voltage-dependent Ca(2+) channels (VDCC), ryanodine receptors (RyRs), large-conductance Ca(2+)-activated K(+) (BK) channels, and small-conductance Ca(2+)-activated K(+) (SK) channels in the regulation of phasic contractions of guinea pig urinary bladder smooth muscle (UBSM). Nisoldipine (100 nM), a dihydropyridine inhibitor of VDCC, abolished spontaneous UBSM contractions. Ryanodine (10 microM) increased contraction frequency and thereby integrated force and, in the presence of the SK blocker apamin, had a greater effect on integrated force than ryanodine alone. Blocking BK (iberiotoxin, 100 nM) or SK (apamin, 100 nM) channels increased contraction amplitude and duration but decreased frequency. The contractile response to iberiotoxin was more pronounced than to apamin. The increases in contraction amplitude and duration to apamin were substantially augmented with ryanodine pretreatment. These results indicate that BK and SK channels have prominent roles as negative feedback elements to limit UBSM contraction amplitude and duration. RyRs also appear to play a significant role as a negative feedback regulator of contraction frequency and duration, and this role is influenced by the activity of SK channels.

Action Potentials↗

Respiratory activities in relation to palatal muscle contraction.

This study investigated the activities of the tensor and levator veli palatini muscles related to respiration. During quiet breathing, no activity was observed in either muscle. With either hypercapnic or hypoxemic condition, the tensor veli palatini muscle exhibited phasic activity during inspiration. The levator veli palatini muscle showed phasic activity during expiration with hypoxemia (PaO2 less than 40 mm Hg). NaCN perfused bilaterally through the carotid sinus induced these respiratory activities. The tensor veli palatini muscle was more sensitive than the levator veli palatini muscle to NaCN.

Animals↗

[Diagnosis of susceptibility for malignant hyperthermia using in-vitro muscle contraction testing in Switzerland].

Malignant hyperthermia is a potentially fatal pharmacogenetic disorder triggered by volatile anesthetics (halothane, enflurane, isoflurane) and/or succinylcholine. The inheritance of malignant hyperthermia susceptibility is thought to be autosomal dominant and the incidence could be as high as 1:10,000. The only generally accepted diagnostic method at present involves a muscle biopsy followed by in-vitro halothane and caffeine contracture tests. 100 individuals from 45 families who were considered to be potentially malignant hyperthermia-susceptible were investigated from 1986 to 1990 by in-vitro muscle contracture tests using the protocol of the European Malignant Hyperthermia Group. Of 45 families analyzed, 28 had at least one person who was susceptible to malignant hyperthermia with a total of 64 malignant hyperthermia-susceptible individuals. 36 subjects in the 45 families were normal. In addition, our study shows that a femoral nerve block can be used in outpatients as a reliable anesthetic technique to perform biopsies from the vastus medialis muscle for malignant hyperthermia screening.

Adolescent↗