RESPIRATORY MUSCLES DURING DEVELOPMENT

Mayo Clinic Coll Of Medicine, Rochester, Rochester MN

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Abstract

DESCRIPTION (Adapted from the applicant's abstract): This investigation will evaluate the underlying relationships between changes in myosin/troponin expression during development and specific morphological and functional characteristics of muscle fibers. In previous studies, the investigators found dramatic changes in myosin heavy chain isoforms, morphology and function in diaphragm fibers during development. This study will explore the relationships between these variables. Specific aim 1 will determine the underlying basis for the postnatal establishment of morphological differences among diaphragm fibers. The hypothesis to be tested is that fiber type differences in postnatal growth reflect differences in synthesis rate of myosin heavy chain (MHC) isoforms that result in a higher MHC content of fibers expressing MHC2x and MHC2b isoforms compared to fibers expressing MHCslow and MHC2A isoforms. Specific aim 2 will determine the underlying basis for the postnatal establishment of fiber type differences in maximum specific force (Po). The hypothesis to be tested is that postnatal increases in Po and adult fiber type difference in Po primarily reflect the influence of varying MHC content. Specific Aim 3 will determine the underlying basis for the postnatal establishment of fiber type differences in Ca+2 sensitivity. The hypothesis to be tested is that fiber type differences in the dependence of force on myoplasmic Ca+2 relate to the expression of different troponin C isoforms; however within a single fiber, Ca+2 sensitivity is modulated by the extent of myosin light chain phosphorylation. Specific Aim 4 will determine the underlying basis for the postnatal establishment of fiber type differences in actomyosin ATPase activity. The hypothesis to be tested is that fiber type differences in actomyosin ATPase activity reflect the combined influence of MHC content, the fraction of cross bridges in the force generating state (alpha-fs) and the apparent rate constant for cross bridge detachment (g-app). With shortening contractions, the increase in actomyosin ATPase activity varies across fiber types, reflecting differences in the impact of active shortening on alpha-fs and g-app.