Previous studies in our laboratory have suggested that the muscle wasting in myotonic dystrophy (DM), the most common form of muscular dystrophy, may result, at least in part, from marked skeletal muscle insulin resistance. The cause for this insulin resistance is unknown. However, the exciting discovery in 1992 that DM results from an unstable CTGn repeat expansion in the 3' untranslated region of a gene on chromosome 19 that codes for a protein kinase (DMPK) has provided an opportunity to investigate the relationship between the insulin resistance and the phenotypic and genotypic features of DM. To date, no studies have shown a conclusive role for DMPK in the pathomechanism of DM. Very recently, a new 3' flanking gene, a homeodomain protein encoding gene, DMAHPO, has been discovered which is closely associated with the region of the DM gene containing the CTGn repeat. The lack of a conclusive role for DMPK in causing the manifestations of DM and the discovery of this new gene, has led us to hypothesize: (1) that the severity of muscle wasting and weakness (phenotype) in DM is directly related to the quantity of the larger mutant DM alleles in both circulating leucocytes and skeletal muscle (genotype); (2) that, as the repeat size increases, the expression of DMAHP, closely situated near the 3' end of the DM gene, becomes altered along with the expression of the DM gene, and contributes to the severity of the muscle wasting and weakness; and, (3) that the skeletal muscle insulin resistance in DM increases in direct proportion to the quantity of larger mutant DM alleles in the symptomatic skeletal muscles. To test this hypothesis we will examine the relationships between: (a) muscle mass and weakness; (b) the quantity of different sizes of mutant DM alleles isolated from leucocytes and muscle; (c) the content of mRNA for DMPK and DMAHP in muscle; (d) insulin resistance (euglycemic insulin infusions combined with regional metabolic studies of the forearm and leg) - in DM patients, in patients with other neuromuscular disorders, and in normals. Our findings will demonstrate if there is a close relationship between the loss of the normal anabolic actions of insulin and the phenotypic and genotypic abnormalities in DM. If so, this suggests that the insulin resistance we previously described in DM may contribute to the severity of the muscle wasting in this disease.
