The diaphragm (DIA) muscle must generate adequate force to sustain ventilation from birth onward despite dramatic changes In muscle contractile and fatigue properties. During the previous grant period, we found that DIA specific force (force/cross-sectional area) and maximum shortening velocity increase during early postnatal development whereas fatigue resistance declines. In preliminary studies, we found that these normal postnatal changes in specific force, maximum shortening velocity and fatigue resistance are correlated to myosin heavy chain (MHC) phenotype transitions. However, we also found that these normal correlations between MHC phenotype and DIA contractile properties are dissociated by denervation and hypothyroidism. One major goal of the proposed studies is to assess alternative mechanisms that might underlie postnatal changes in DIA contractile and fatigue properties.
The specific aims of the proposal are to examine the following hypotheses: 1) Perturbations of normal postnatal MHC phenotype transitions do not exert predictable effects on DIA contractile and fatigue properties; 2) The lower specific force of neonatal DIA reflects fewer cross-bridges available for attachment (increased interstitial space and/or reduced myofibrillar density) and a lower fraction of cross-bridges in the force generating state due to a reduced rate constant for cross-bridge attachment; 3) The left-shifted force-pCa2+ relationship of neonatal DIA reflects an increase in the relative number of attached cross-bridges (stiffness) at any given submaximal myoplasmic [Ca2+] (pCa2+); 4) The slower maximum unloaded shortening velocity (VO) of neonatal DIA reflects the lower actomyosin ATPase activity and/or a slower rate constant for cross-bridge detachment; and 5) Postnatal changes in DIA fatigue resistance are better indexed by changes in actomyosin ATPase activity than by changes in SDH activity.
These specific aims will be examined under three experimental conditions where changes in DIA contractile and fatigue properties and MHC phenotype transitions occur: 1) Normal postnatal development; 2) Denervation of the right hemidiaphragm at postnatal day 7; and 3) Hypothyroidism induced during gestation. Denervation and hypothyroidism are specifically used as experimental perturbations to explore the underlying mechanisms for early postnatal changes in DIA contractile and fatigue properties. A variety of contractile, metabolic and ultrastructural properties of developing DIA will be examined under these different experimental conditions. The results of these studies will provide a better understanding of the underlying mechanisms that account for postnatal changes in DIA contractile and fatigue properties.
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