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Muscle Biology Research

Muscle Biology Research (Larsson): The overall goal of the research is to have a detailed understanding of how muscle contraction is regulated at the cellular and molecular levels by myofibrillar protein isoforms, and to transfer this information from basic science into practical clinical knowledge in muscle disorders affecting myosin and myosin-associated proteins in humans. For several reasons, specific interest is focused on the molecular motor protein myosin and myosin associated proteins. First, myosin is the molecular motor that converts free energy derived from its hydrolysis of ATP into mechanical work. Second, the isoform diversity of myosin isoforms has a major impact on muscle contractility since one of the most important designs parameters of skeletal muscle, speed of contraction, is primarily regulated by the expression of myosin heavy chain (MyHC) isoforms. Third, a large proportion of patients evaluated for skeletal muscle weakness still fail to receive specific diagnosis, but improvement of molecular diagnostic tools together with structure-function analyses of the motor protein myosin will provide the basis for screening patients for possible skeletal myosinopathies. The coding sequence for the adult MyHC isoforms is among the most heavily amplified in mammalian species. The resulting polypeptide generally accounts for 15-25% of the total body protein, and the large size of the 17p13.1 locus within the MyHC gene would predict a prominent role for MyHC mutations in human myopathy. The clinical research is focusing on: (1) an acquired myosinopathy, i.e., the generalized muscle weakness or acute quadriplegia in intensive care unit patients, i.e., a disease associated with a complete or partial depletion of all myosin and myosin-associated proteins in limb and trunk muscles, and (2) hereditary myosinopathies.
A significant portion of the basic research has been devoted to improve our understanding of regulation and modulation of muscle contraction by myofibrillar proteins, such as myosin heavy chain (MyHC), myosin light chain (MyLC), myosin binding protein C (MyBP-C), and troponin isoforms. The maximum velocity of unloaded shortening (V0) is one of the most important design parameters of skeletal muscle, since muscles develop their maximum power at a shortening velocity of approximately one-third V0. Thus, to generate power optimally over a wide range of movements, it is crucial to be able to recruit motor units/muscle fibers with a wide V0 range, which power different movements optimally. Studies of single fibers from muscles of small amphibians, avians or laboratory mammals form the basis of our knowledge of the regulatory influence of myosin isoforms on V0, and the rat is the most extensively characterized species with regard to studies on regulation of muscle contraction and myofibrillar protein isoform expression. It is well known, however, that body size affects speed of skeletal muscle shortening, i.e., large mammals are characterized by lower stride frequencies and slower limb movements than small mammals, and speed of muscle contraction scales with body size. Generalization of results from small mammals, such as the rat, to larger mammals, such as man, constituting a 250-fold difference in body size may accordingly not always be valid. Therefore, it has been very important to develop or modify techniques that make it possible to study regulation of muscle contraction in humans under standardized and controlled conditions. The development of different methods to study regulation of human muscle contraction is illustrated by the applicant´s research on mechanisms underlying the aging-related motor handicap at the skeletal muscle level, i.e., a research field which is of significant interest in both basic and clinical science.

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