Principal Investigator: LaDora Thompson, Ph.D.
Inactivity induces a set of pronounced physiological adaptations, especially in skeletal muscle. The progressive decline in skeletal muscle mass and function due to disuse contributes significantly to the loss of functional autonomy in individuals. This functional decline is further complicated in individuals with muscle disease, such as muscular dystrophy. Although the overall functional and biochemical alterations in muscle have been studied following periods of inactivity, the molecular mechanisms implicated remain unclear. Understanding the underlying molecular mechanisms will be essential for targeting appropriate therapeutic modalities, especially during periods of unwanted, extended disuse in individuals with muscle diseases. There is a preponderance of evidence that disuse (in healthy animal models) results in changes that are muscle-specific. In other words, the soleus muscle (composed of slow-twitch fibers) and the semimembranosus muscle (composed of fast-twitch fibers) adapt to disuse, but the time-course of adaptation is very different between these two muscles. This muscle-specific adaptation suggests a remarkable coordinated regulation of gene and protein expression. Thus, the overall goal of the present proposal is to identify the profiles of differential expression of mRNAs concomitant with profiles of differential expression of proteins. We hypothesize that there will be a correlation between the gene and protein expression patterns and these patterns will be muscle-specific. In the present proposal, we will induce muscle disuse with the established hindlimb unweighting model. We will perform targeted gene expression analysis and protein profiles at prescribed time points during hindlimb unweighting. We will identify novel changes in gene expression and protein profiles in two different muscles that are composed of different skeletal muscle fiber type compositions. The following aims will be pursued. (1) Determine the expression profile of a broad range of transcripts in skeletal muscle following three distinct periods of disuse. (2) Determine the disuse-associated skeletal muscle protein expression patterns in muscles. (3) Determine the relationship between the gene and protein expression profiles in skeletal muscle following three distinct periods of disuse. This information will be of considerable importance to our understanding of how disuse stimulates muscle atrophy, identifying possible molecular and cellular mechanisms responsible for muscle-specific adaptation and to the development of novel therapeutic strategies aimed at maintaining or restoring muscle mass.