| Skeletal muscle is unique among the tissues of the body in that it can readily change its structure when subject to different mechanical conditions. Muscles can adapt to overload or disuse by hypertrophy and atrophy, to alterations in use frequency by changing fiber type and mitochondrial numbers, and to alterations in length by subtracting or adding sarcomeres (the fundamental units of muscle). Thus skeletal muscles are able to sense various mechanical stimuli and respond appropriately.This dissertation delves into the question of how muscles sense and respond to mechanical stimuli. Desmin is an intermediate filament specific to skeletal muscle, whose connections between the sarcolemma, z-disks, and nuclei make it ideally located to transmit and sense stresses. Previous studies have demonstrated that stretch-induced JNK signaling is greatly attenuated in skeletal muscle from desmin knockout mice. While one could conclude that JNK signaling is directly dependent on desmin's presence, desmin has also been shown to be essential for proper nuclear strain transmission. Thus JNK signaling could alternatively depend on proper nuclear mechanics.To clarify how desmin contributes to signaling, novel methods were used to allow observation of the desmin network during eccentric contraction. Desmin filament disassembly or remodeling during eccentric exercise could be the means by which the high stresses of the eccentric contractions are transduced into a biochemical signal however, no such changes in the desmin network were observed. Then, to investigate whether stretch of the nucleus was a requirement for stretch-induced JNK signaling, studies of nesprin-1 knockout mice were performed. The muscle fibers from these mice exhibited reduced strain transmission to the nuclei, as in the desmin knockout. Upon stretch, however, the JNK signaling levels in the wild-type and nesprin-1 knockout muscles were the same. Thus normal stretch-induced JNK signaling can occur in the absence of normal nuclear stretch. Moreover, stretch-induced JNK signaling appears to depend on desmin, although it remains unclear how desmin mediates JNK signaling. |
