Skeletal muscle provides an organism with a means of reacting to its environments. It is a complex and versatile tissue that is capable of change under a variety of conditions. For example extensive literature has shown muscle transformation from slow-to-fast by decreased motor nerve activity, hypogravity, physical inactivity and in diseased states. Similarly muscle transformation from fast-to-slow can be evoked by increased muscle nerve activity or exercise. The multitude of protein changes that has been identified by muscle transformation indicates it is a complex process that can change a wide variety of the muscle tissues architecture, metabolism and function. Proteomic profiling of two very different diseased states has allowed the identification of muscle transformation occurring in opposite directions. Myotonia a common feature found in myotonic dystrophies is characterized by skeletal muscle membrane hyperexcitability. Proteomic profiling was carried out on three independent spontaneous mutant mice and allowed us to compare secondary effects of hyperexcitabilty on skeletal muscle. Severly myotonic mice MTO and ADR displayed a muscle transformation from fast-to-slow. The more mildly affected MTO*5J mutant showed slight changes in proteins associated with fast and slow muscle. In comparison to the myotonic diseased state we carried out proteomic profiling of skeletal muscle tissue from the Wobbler mouse; an animal model of motor neuron degeneration. In contrast to myotonia the WR protein profile displayed a slow-to-fast muscle transformation. The detailed MS-based analysis of diseased skeletal muscle has shown that proteomics is highly suitable to determine change in the isoform expression pattern of muscle proteins. Identified proteins can be used as potential factors for the establishment of comprehensive biomarker signature of myotonic and motor neuron diseases.