SYNAPTIC ACTIVITY AND CONNECTIVE-TISSUE REMODELING IN DENERVATED FROG-MUSCLE

Denervation of skeletal muscle results in dramatic remodeling of the c ellular and molecular composition of the muscle connective tissue. Thi s remodeling is concentrated in muscle near neuromuscular junctions an d involves the accumulation of interstitial cells and several extracel lular matrix molecules. Given the role of extracellular matrix in neur ite outgrowth and synaptogenesis, we predict that this remodeling of t he junctional connective tissue directly influences the regeneration o f the neuromuscular junction. As one step toward understanding the rol e of this denervation-induced remodeling in synapse formation, we have begun to look for the signals that are involved in initiating the jun ctional accumulations of interstitial cells and matrix molecules. Here , the role of muscle inactivity as a signal was examined. The distribu tions of interstitial cells, fibronectin, and tenascin were determined in muscles inactivated by presynaptic blockade of muscle activity wit h tetrodotoxin. We found that blockade of muscle activity for up to 4 wk produced neither the junctional accumulation of interstitial cells nor the junctional concentrations of tenascin and fibronectin normally present in denervated frog muscle. In contrast, the muscle inactivity induced the extrajunctional appearance of two synapse-specific molecu les, the acetylcholine receptor and a muscle fiber antigen, mAb 3B6. T hese results demonstrate that the remodeling of the junctional connect ive tissue in response to nerve injury is a unique response of muscle to denervation in that it is initiated by a mechanism that is independ ent of muscle activity. Thus connective tissue remodeling in denervate d skeletal muscle may be induced by signals released from or associate d with the nerve other than the evoked release of neurotransmitter.