Structural and functional roles of desmin in mouse skeletal muscle.

摘要

Several observations have raised the possibility that desmin, a muscle-specific intermediate filament, plays structural, mechanical, and myogenic roles in skeletal muscle. However, there is very little direct evidence to prove or disprove any of these hypothesized physiological roles. This dissertation attempts to understand structural and functional roles of desmin through a series of experiments using the desmin-null mouse model.; Hindlimb immobilization of desmin-null and wild-type mice revealed that the absence of desmin did not significantly affect the ability of muscles to remodel in response to chronic stretch or shortening. In contrast, the absence of desmin dramatically altered the mechanical properties muscle, particularly in response to eccentric contractions. Specifically, desmin-null muscles generated less stress than wild-type muscles, yet appeared to be better protected from injury. These two early studies revealed that changes in mechanical phenotypic effected by the absence of desmin were more dramatic than myogenic alterations. The remainder of the dissertation consequently probed the functional role of desmin under mechanical loading conditions.; A sterological analysis of revealed that desmin played a structural role in limiting myofibrillar mobility. To determine whether this structural role corresponded to a role in mechanical function, a novel confocal system was developed to measure single muscle fiber mechanical properties during passive loading, while simultaneously imaging protein interactions within the cell. The system was utilized to examine hypothesized desmin-mediated connections within the muscle fiber.; Analysis of Z-disk connectivity confirmed that desmin was responsible for maintaining Z-line alignment during mechanical loading, and potentially influenced mechanical function by regulating cell volume. On the other hand, even in the absence of desmin, costamere complexes in the cell membrane remained firmly secured to the sarcomere lattice within the cell. Finally, the absence of desmin affected nuclear geometry during passive stretch, having significant implications for the initiation of mechanical signal transduction pathways.