Gene and protein expression in denervated atrophic and hypertrophic skeletal muscle

Sammanfattning: Following denervation skeletal muscles change their functional and structural properties. Some changes resemble conditions in developing muscles and may be important for reinnervation. Due to inactivity following denervation most skeletal muscles loose muscle mass and become atrophic. The hemidiaphragm muscle, however, undergoes a phase of transient hypertrophy following denervation, gaining weight during the first 6-10 days followed by a decrease in weight. In this thesis the expression (mRNA, protein and protein phosphorylations) of potential factors involved in the regulation of muscle mass were examined in denervated hind-limb and hemidiaphragm muscles.NIFK is a protein that associates with Ki67, a protein expressed predominantly in proliferating cells. The mRNA expression of NIFK was upregulated in denervated atrophic muscles but unaltered in denervated hypertrophic muscles, suggesting a potential role in the regulation of skeletal muscle mass (Paper I). p38 MAPK has previously been implicated in both anabolic and catabolic processes. Its substrate MK2 becomes phosphorylated at two sites, one of which is suggested to be important for nuclear export. MK2 phosphorylation at this site correlated with muscle weight in both atrophic and hypertrophic denervated muscles and may thus have a role in atrophy and hypertrophy (Paper III). Factors regulating protein synthesis are likely to play a role in atrophy and hypertrophy and many signaling pathways appear to converge on the formation of the translation initiation complex. The protein expression and phosphorylation status of several components in both Wnt and Akt signaling pathways indicate increased protein synthesis in denervated atrophic muscles as well as in denervated hypertrophic muscles (Papers II, IV and V). This suggests that increased protein degradation is more important than decreased protein synthesis for the loss of muscle mass in denervated atrophic muscles.