The main objective of the proposed research is to examine mechanisms of skeletal muscle atrophy in response to denervation. Muscle atrophy (wasting) is a significant problem associated with reduced muscle use (e.g. bed-rest, nerve injury, weightlessness). Atrophy associated with reduced muscle load-bearing can be largely attributed to accelerated protein destruction in the cytoplasm (soluble portion) of the cell, whereas with nerve eradication a primary site of protein destruction appears to be the lysosome. The focus of this proposal is to examine the role of the intact nerve in preventing a recruitment of the lysosomal process for protein destruction. These issues will be examined by comparing the time course of atrophy following denervation at sites proximal and distal to the soleus muscle. Levels of glucose transporter protein (GLUT-4 isoform), one determinant of glucose transport capacity, will be used to assess the effect of lysosomal proteolysis on a specific membrane protein. Results from this study could have significant bearing on developing future approaches to reducing muscle atrophy in a variety of conditions associated with nerve damage. If factors within the nerve attenuate protein destruction in the lysosome, then potentially such factors could be injected directly into muscle to reduce muscle loss, especially with nerve injury or even with reduced muscle use.
