The overall goal of the applicant's 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 clinical knowledge in muscle disorders affecting myosin and myosin-associated proteins in humans. 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 analyzes of the motor protein myosin will provide the basis for screening patients for possible skeletal muscle myosinopathies. The maximum velocity of unloaded shortening (Vo) 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 Vo and detailed understanding of Vo regulation and modulation by myofibrillar proteins is of significant importance in both basic and clinical science. This project, focussing on changes in shortening velocity associated with a change in body size (scaling), constitutes a significant component in our attempt to further elucidate the regulation and modulation of muscle contraction in mammalian skeletal muscle. Our knowledge on the regulation of muscle contraction and expression of myofibriilar protein isoforms is primarily based on observations in rodents, but there is reason to question whether results from small mammals, such as mice and rats, can be generalized to larger mammals, such as humans, constituting a 3000-fold difference in body size. There is accordingly a significant need for projects focusing on the mechanisms underlying scaling-related differences in shortening velocity at the cellular and molecular levels. A combination of biochemical, mass spectrometry, molecular and cellular-physiological techniques will be used to explore the enzymatic activity, structure and function of different motor protein isoforms and how these characteristics regulate and modulate shortening velocity in mammals with a 100,000-fold body size range.
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