Molecular Control Mechanisms in Striated Muscle Contraction addresses the molecular mechanisms by which contraction of heart and skeletal muscles is regulated, as well as the modulation of these mechanisms by important (patho)physiological variables such as ionic composition of the myoplasm and phosphorylations of contractile and regulatory proteins. For the novice, this volume includes chapters that summarize current understanding of excitation-contraction coupling in striated muscles, as well as the compositions and structures myofibrillar thick and thin filaments. For the expert, this volume presents detailed pictures of current understanding of the mechanisms underlying the CA2+ regulation of contraction in heart and skeletal muscles and discusses important directions for future investigation.

Striated muscle is the most common muscle type in the vertebrate body. This book describes in molecular terms the components and intracellular events responsible for the contraction and relaxation of striated muscle. The topic is introduced with a discussion of motile systems occurring throughout the biological world and their relation to the highly specialised contractile system of muscle. Professor Perry then goes on to discuss the mechanochemical process and the regulatory roles of calcium, I filament proteins and phosphorylation. The book ends with an examination of the role of dystrophin and its implications in Duchenne muscular dystrophy, the most common form of muscle disease. Molecular Mechanisms in Striated Muscle will provide an important source of information and current theory for researchers and postgraduate students in muscle physiology, biochemistry and medicine.

There has been a lot of debate concerning the nature of the molecular mechanism that produces filament sliding and muscle shortening. This book presents the different kinds of structural and mechanical evidence in favour of the swinging of myosin heads on actin during the contractile cycle.

This volume presents the proceedings of a muscle symposium, which was supported by the grant from the Fujihara Foundation of Science to be held as the Fourth Fujihara Seminar on October 28 -November 1, 2002, at Hakone, Japan. The Fujihara Seminar covers all fields of natural science, while only one proposal is granted every year. It is therefore a great honor for me to be able to organize this meeting. Before this symposium, I have organized muscle symposia five times, and published the proceedings: " Cross-bridge Mechanism in Muscle Contraction (University of Tokyo Press, 1978), "Contractile Mechanisms in Muscle" (plenum, 1984); "Molecular Mechanisms of Muscle Contraction" (plenum, 1988); "Mechanism of MyofIlament Sliding in Muscle contraction" (plenum, 1993); "Mechanisms of Work Production and Work Absorption in Muscle" (plenum, 1998). As with these proceedings, this volume contains records of discussions made not only after each presentation but also during the periods of General Discussion, in order that general readers may properly evaluate each presentation and the up-to-date situation of this research field. It was my great pleasure to have Dr. Hugh Huxley, a principal discoverer of the sliding fIlament mechanism in muscle contraction, in this meeting. On my request, Dr. Huxley kindly gave a special lecture on his monumental discovery of myofIlament-lattice structure by X-ray diffraction of living skeletal muscle. I hope general readers to learn how a breakthrough in a specific research field can be achieved.

Understanding the molecular mechanism of muscle contraction started with the discovery that striated muscle is composed of interdigitating filaments which slide against each other. Sliding filaments and the working-stroke mechanism provide the framework for individual myosin motors to act in parallel, generating tension and loaded shortening with an efficient use of chemical energy. Our knowledge of this exquisitely structured molecular machine has exploded in the last four decades, thanks to a bewildering array of techniques for studying intact muscle, muscle fibres, myofibrils and single myosin molecules. After reviewing the mechanical and biochemical background, this monograph shows how old and new experimental discoveries can be modelled, interpreted and incorporated into a coherent mathematical theory of contractility at the molecular level. The theory is applied to steady-state and transient phenomena in muscle fibres, wing-beat oscillations in insect flight muscle, motility assays and single-molecule experiments with optical trapping. Such a synthesis addresses major issues, most notably whether a single myosin motor is driven by a working stroke or a ratchet mechanism, how the working stroke is coupled to phosphate release, and whether one cycle of attachment is driven by the hydrolysis of one molecule of ATP. Ways in which the theory can be extended are explored in appendices. A separate theory is required for the cooperative regulation of muscle by calcium via tropomyosin and troponin on actin filaments. The book reviews the evolution of models for actin-based regulation, culminating in a model motivated by cryo-EM studies where tropomyosin protomers are linked to form a continuous flexible chain. It also explores muscle behaviour as a function of calcium level, including emergent phenomena such as spontaneous oscillatory contractions and direct myosin regulation by its regulatory light chains. Contraction models can be extended to all levels of calcium-activation by embedding them in a cooperative theory of thin-filament regulation, and a method for achieving this grand synthesis is proposed. Dr. David Aitchison Smith is a theoretical physicist with thirty years of research experience in modelling muscle contractility, in collaboration with experimental groups in different laboratories.

The inflammatory cytokine, interferon gamma, IFN-gamma orchestrates a diverse array of fundamental physiological processes and exhibits complex effects on myogenesis. IFN-gamma also induces the class II transactivator, CIITA, which is a critical mediator of IFN-gamma mediated repression and activation. The aims in my dissertation are directed towards understanding the role of IFN-gamma and CIITA in muscle. Stimulation by IFN-gamma in skeletal muscle cells induces CIITA expression as well as MHC class II gene expression. We show that the IFN-gamma induced inhibition of myogenesis is mediated by CIITA, which specifically interacts with myogenin. CIITA acts by both, repressing the expression and inhibiting the activity of myogenin at different stages of myogenesis. The IFN-gamma mediated repression is reversible, with myogenesis proceeding normally upon removal of IFN-gamma. We also show that CIITA is indispensible for the inhibition of myogenesis. To gain a mechanistic insight into the IFN-gamma induced repression of myogenesis, we have discovered that IFN-gamma and CIITA inhibit myogenesis by modifying gene regulation in a muscle cell subject to inflammation. We show that CIITA first interacts with JARID2, a non catalytic subunit of PRC2 complex, which induces a paused RNAPII, phosphorylated at serine 5 and then interacts with the catalytic subunit EZH2, in a JARID2 dependent manner. Our data show that both CIITA and IFN-gamma block myogenesis by the induction and recruitment of the PRC2 complex, which is normally silenced in a differentiating muscle cell. One of my dissertation aims sheds light on the silencing of CIITA in Rhabdomyosarcoma. Silencing of CIITA prevents the expression of MHC Class I and II genes. We have found that IFN-gamma signaling is intact in these cells, but pSTAT1 and IRF1 do not bind to the CIITA PIV promoter. The CIITA promoter is not hypermethylated in RD (ERMS) cells, but shows a modestly enhanced methylation status in SJRH30 (ARMS) cells. We have also observed that histone acetylation, which normally increases on the CIITA PIV promoter following IFN-gamma treatment, is blocked in both types of RMS cells. Further, our studies also impart a novel role for IFN-gamma and CIITA in inhibiting the IGF induced activation of muscle specific genes. Our data show that IFN-gamma does not block the signaling cascade of IGF. However, blocking exogenous IFN-gamma restores IGF activation of muscle specific genes. My dissertation also reveals an important role for the FACT complex in the early steps of gene activation through its histone chaperone activities that serve to open chromatin structure and facilitate transcription promoting muscle differentiation. We show that myogenin interacts with the FACT complex and the recruitment of FACT complex to muscle specific genes is dependent on myogenin. The final aim in my dissertation highlights the distinct binding profiles of the MRFs and E proteins during proliferation and differentiation. Our sequential ChIP assays show that MYOD, MYOG, and MYF5 co-occupy promoters. Taken together, my dissertation provides a comprehensive understanding of the molecular mechanisms during myogenesis and reveals the deleterious effects of chronic inflammation in skeletal muscle.