GENE-EXPRESSION IN SKELETAL-MUSCLE IN RESPONSE TO STRETCH AND FORCE GENERATION

Striated muscle is a tissue in which gene expression is influenced to a large extent by mechanical signals. This includes the regulation of gene expression-associated muscle fiber phenotype determination, which depends on which protein isoform genes are transcribed, as well as muscle fiber mass accretion, which appears to involve some translational regulation. Although muscle synthesizes a set of highly specialized proteins it has a remarkable ability to adapt by expressing different isoforms of the same protein so that it acquires the appropriate contractile characteristics. Our work has focused on the myosin heavy chain (HC) genes as these encode the myosin cross bridge, which is responsible for muscle intrinsic velocity of contraction and economy of force development. RNA analyses after cast immobilization of the limb with the muscle in the lengthened or shortened position and/or with electrical stimulation were used to determine the effects of altered mechanical signals on gene transcription. When the soleus muscle was immobilized in the shortened position in the young animal it did not fully differentiate into a slow postural-type muscle. Even in the adult, the soleus muscle if deprived of stretch and contractile activity switches back to transcribing the fast myosin HC gene. The converse was true when the fast rabbit tibialis anterior was subjected to immobilization in the lengthened position and/or electrical stimulation. Both stretch alone and stimulation alone caused repression of the fast type and activation of the slow myosin genes. The reprogramming of the fast muscle was more complete when the stretch was combined with stimulation. When subjected to stretch and mechanical overload skeletal muscle apparently adapts to a more postural type of role by expressing the slow isoform genes as well as higher levels of mitochondrial genes. As far as muscle mass accretion is concerned, stretch combined with force generation caused the tibialis anterior in the adult rabbit to increase in mass by 30% within 4 days. This was associated with an increase in total muscle RNA of 250%, which reflects a large increase in ribosomes available to translate whatever message is available. The possible link between the mechanical signal and the activation or repression of certain muscle genes is discussed.