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The calcineurin–NFAT (nuclear factor of activated T-cells) signalling pathway is involved in the regulation of activity-dependent skeletal muscle myosin heavy chain (MHC) isoform type expression. Emerging evidence indicates that nitric oxide (NO) may play a critical role in this regulatory pathway. Thus, the purpose of this study was to investigate the role of NO in activity-induced calcineurin–NFATc1 signalling leading to skeletal muscle faster-to-slower fibre type transformations in vivo. Endogenous NO production was blocked by administering L-NAME (0.75 mg ml(−1)) in drinking water throughout 0, 1, 2, 5 or 10 days of chronic low-frequency stimulation (CLFS; 10 Hz, 12 h day(−1)) of rat fast-twitch muscles (L+Stim; n = 30) and outcomes were compared with control rats receiving only CLFS (Stim; n = 30). Western blot and immunofluorescence analyses revealed that CLFS induced an increase in NFATc1 dephosphorylation and nuclear localisation, sustained by glycogen synthase kinase (GSK)-3β phosphorylation in Stim, which were all abolished in L+Stim. Moreover, real-time RT-PCR revealed that CLFS induced an increased expression of MHC-I, -IIa and -IId(x) mRNAs in Stim that was abolished in L+Stim. SDS-PAGE and immunohistochemical analyses revealed that CLFS induced faster-to-slower MHC protein and fibre type transformations, respectively, within the fast fibre population of both Stim and L+Stim groups. The final fast type IIA to slow type I transformation, however, was prevented in L+Stim. It is concluded that NO regulates activity-induced MHC-based faster-to-slower fibre type transformations at the transcriptional level via inhibitory GSK-3β-induced facilitation of calcineurin–NFATc1 nuclear accumulation in vivo, whereas transformations within the fast fibre population may also involve translational control mechanisms independent of NO signalling.

The stability properties of linear switched systems consisting of both Hurwitz stable and unstable subsystems are investigated by using piecewise Lyapunov functions incorporated with an average dwell time approach. It is shown that if the average dwell time is chosen sufficiently large and the total activation time ratio between Hurwitz stable and unstable subsystems is not smaller than a specified constant, then exponential stability of a desired degree is guaranteed. The above result is also extended to the case where nonlinear norm-bounded perturbations exist.

The purpose of this study was to determine whether induced expression of the Ca2+ buffering protein parvalbumin (PV) in slow-twitch fibres would lead to alterations in physiological, biochemical and molecular properties reflective of a fast fibre phenotype. Transgenic (TG) mice were generated that overexpressed PV in slow (type I) muscle fibres. In soleus muscle (SOL; 58 % type I fibres) total PV expression was 2- to 6-fold higher in TG compared to wild-type (WT) mice. Maximum twitch and tetanic tensions were similar in WT and TG but force at subtetanic frequencies (30 and 50 Hz) was reduced in TG SOL. Twitch time-to-peak tension and half-relaxation time were significantly decreased in TG SOL (time-to-peak tension: 39.3 +/- 2.6 vs. 55.1 +/- 4.7 ms; half-relaxation time: 42.1 +/- 3.5 vs. 68.1 +/- 9.6 ms, P0.05 for TG vs. WT, respectively; n = 8-10). There was a significant increase in expression of type IIa myosin heavy chain (MHC) and ryanodine receptor at the mRNA level in TG SOL but there were no differences in MHC expression at the protein level and thus no difference in fibre type. Whole muscle succinate dehydrogenase activity was reduced by 12 +/- 0.4 % in TG SOL and single fibre glycerol-3-phosphate dehydrogenase activity was decreased in a subset of type IIa fibres. These differences were associated with a 64 % reduction in calcineurin activity in TG SOL. These data show that overexpression of PV, resulting in decreased calcineurin activity, can alter the functional and metabolic profile of muscle and influence the expression of key marker genes in a predominantly slow-twitch muscle with minimal effects on the expression of muscle contractile proteins.

Different patterns of motor nerve activity drive distinctive programs of gene transcription in skeletal muscles, thereby establishing a high degree of metabolic and physiological specialization among myofiber subtypes. Recently, we proposed that the influence of motor nerve activity on skeletal muscle fiber type is transduced to the relevant genes by calcineurin, which controls the functional activity of NFAT (nuclear family of activated T cell) proteins. Here we demonstrate that calcineurin-dependent gene regulation in skeletal myocytes is mediated also by MEF2 transcription factors, and is integrated with additional calcium-regulated signaling inputs, specifically calmodulin-dependent protein kinase activity. In skeletal muscles of transgenic mice, both NFAT and MEF2 binding sites are necessary for properly regulated function of a slow fiber-specific enhancer, and either forced expression of activated calcineurin or motor nerve stimulation up-regulates a MEF2-dependent reporter gene. These results provide new insights into the molecular mechanisms by which specialized characteristics of skeletal myofiber subtypes are established and maintained.

For linear systems with parameter uncertainties and subject to state saturation, we establish results concerning the global asymptotic stability of an equilibrium. In addition to providing a means for a qualitative analysis, these results also enable us to address the stabilizability of such systems by means of linear state feedback. Systems of the type considered herein capture two important phenomena commonly encountered in the modelling process: (i) system parameter uncertainties (which in the present case are modelled by means of interval matrices), and (ii) operation of systems over a wide range (which in the present case is accounted for by state saturation nonlinearities). We demonstrate the applicability of the present results by means of several specific examples.

In this paper, in the case when there are no modelling errors, bursting phenomena in extended-least-squares- (ELS-) based self-tuning control are analysed. It is shown that in the absence of external excitation and without imposing structural conditions on the system model, bursts of the tracking error and consequently drift of the parameter estimates are possible. By analysing the possible occurrence of bursting, an upper bound on the convergence rate of the tracking error is established. It is demonstrated that it is the self-excitation mechanism which provides global stability of the adaptive system. In other words, the possible instability of the adaptive loop generates a bounded condition number of the covariance matrix. This in turn implies stabilization of the adaptive system. In this paper we also discuss a stochastic gradient algorithm with a convergence rate similar to that presently established for the ELS-based self-tuning controller.

The extent to which the remaining active or passive components of muscle mechanical stress not associated with weightbearing are involved in preserving muscle morphological and functional characteristics in the rodent hindlimb suspension model is not known. Such information would be relevant to the construction of appropriate countermeasures for the disuse atrophy associated with muscle unloading. This question was addressed by superimposing 2 weeks of hindlimb suspension and neuromuscular quiescence, achieved by the chronic neural application of the sodium channel blocker tetrodotoxin. A major portion of the muscle size characteristics of the fast anti-gravity gastrocnemius and plantaris, and the functional characteristics of the plantaris, were maintained by the full range voluntary activity remaining after suspension. Muscle mass of the slow soleus was compromised regardless of this residual activity. Indeed, for fast ankle extensors, hindlimb unloading resembles more closely a model of normal usage than of disuse, but for slow extensors this condition appears to be extremely detrimental.

The technique of laser flow cytofluorometry has been used to monitor the arrival in G1 and the subsequent progression through the cell cycle of HTC cells accumulated in metaphase with colcemid alone or after treatment with hydroxyurea and Nocodazole. Under the experimental conditions used in this study, the latter procedure gives much better results, avoiding in particular the extensive formation of micronucleated cells. Aphidicolin, an inhibitor of DNA polymerase, in combination with Nocodazole, provides a useful method to tightly synchronize these cells at the G1/S border.

New results for stability, instability, and boundedness of composite or interconnected systems are presented and a procedure for stabilizing such systems is established. Both time domain and frequency domain methods are employed. The results are applied to several specific examples. Neue Ergebnisse fur Stabilitat, Instabilitat und Unbeschranktheit zusammengesetzter oder verbundener Systeme werden dargelegt, und ein Verfahren zur Stabilisierung solcher Systeme wird hergeleitet. Zeit- sowie Frequenzmethoden werden herangezogen. Die Ergebnisse werden auf einige spezifische Beispiele angewendet.

Sufficient conditions for the Lyapunov stability, with probability one, of several classes of (a) continuous-parameter stochastic composite systems, and, (b) discrete-parameter stochastic composite systems are established. In all cases the objective is the same: to analyze the stability of large-scale composite systems in terms of their lower order subsystems and in terms of their interconnecting structure. In order to demonstrate the usefulness of the present approach, several specific examples are considered. Fur mehrere Klassen zusammengesetzter slochastischer Systeme a) mit stetigen, b) mit diskreten Parametern werden hinreichende Bedingungen fur die Ljapunow-Stabilitat aufgestellt. In alien Fallen ist das Ziel dasselbe: Die Stabilitat umfangreicher zusammengesetzter Systeme in Ausdrucken, die sich aus ihren Teilsystemen niedrigerer Ordnung ergeben, und in solchen, die ihre Zusammenhangstruktur widerspiegeln, zu erfassen. Um die Nutzlichkeit der Vorgehensweise zu demonstrieren, werden mehrere spezielle Beispiele betrachtet.

New results for the second-order stochastic input-output stability and instability of large classes of continuous time and discrete time interconnected stochastic systems are established. The analysis is accomplished in terms of lower order subsystems and in terms of system interconnecting structure. When appropriate, frequency domain interpretations are emphasized. The method of analysis advanced herein is applied to three specific examples. Es werden neue Ergebnisse zur stochastischen Eingabe-Ausgabe-Stabilitat zweiter Ordnung sowie zur Instabilitat von grosen Klassen gekoppelter stochastischer Systeme mit stetiger und diskreter Zeit hergeleitet. Bei der Analyse wird von Teilsystemen niederer Ordnung und von der Koppelstruktur des Systems ausgegangen. Wo das am Platze ist, werden Frequenzbereich-Interpretationen angegeben. Die hier gegebene Untersuchungsmethode wird auf drei konkrete Beispiele angewendet.