HIV positive subjects undergoing prolonged therapy with zidovudine (AZT) exhibit symptoms of myopathy characterized by tenderness and pain in the proximal limb musculature, ambulatory difficulties, and diminished strength, absent in untreated HIV subjects. Improvements in symptoms are temporally related to withdrawal from therapy. The lethal prognosis of AIDS compels patients exposed to the virus to seek therapy with reverse transcriptase inhibitors such as AZT. It is essential to understand the pathological effects this drug exerts upon afflicted individuals to mediate therapy tolerance. the functional consequences to muscle performance and cellular energetics with AZT therapy present a novel and clinically important arena for research in light of the value of this drug to AIDS therapy. An animal model has been developed by chronic administration of AZT to adult mice which provides a unique opportunity to examine changes in muscle myopathy, metabolism, and performance as a consequence of therapy. the proposed work uses histology, biochemistry, muscle mechanics, and 31P- NMR spectroscopy to study representative fast and slow twitch muscles in mice. The first specific aim characterizes the AZT-induced myopathy by: a) testing the hypothesis that AZT therapy results in an increase in the percentage of ragged red fibers and a decrease in oxidative capacity; b) testing the hypothesis that AZT therapy results in muscle necrosis or increases in glycolysis; and c) determining if the levels of phosphorus metabolites change in response to AZT administration. The second specific aim evaluates the consequences of AZT administration to muscle function during the time course of therapy and is divided into three parts: a) to determine if AZT treatment will result in alterations in muscle performance (strength and exercise tolerance); b) to determine if treated mice have a lower aerobic capacity and slower rate of recovery from exercise; and c) to determine the time course of the functional changes in cellular energetics. the third specific aim will determine if muscle tissue can compensate for the effects of AZT by changes in energy demand and/or supply: a) to determine if the contractile proteins (ATPase) composition are altered in treated muscles; b) to determine if decreased oxidative capacity is compensated by glycolytic pathways; and c) to determine if disruption of mitochondrial function by AZT therapy results in compensatory changes in enzymes for oxidative metabolism. Diagnosis and treatment of AZT-induced myopathies will benefit from understanding the mechanism of action on healthy muscle, independent of HIV complications. the proposed experiments will be of wide significance on three levels. First, they will systematically define pathophysiological changes which occur in skeletal muscle in response to a reverse transcriptase inhibitor. Secondly, the use of 31P-NMR spectroscopy to non-invasively evaluate the progression of the myopathy may become an important tool in assessment of this condition in human subjects. Lastly, biochemically assays on an induced myopathy in otherwise healthy muscle will permit evaluation of the compensatory mechanisms invoked to maintain function in the pathophysiological state.
| Wiseman, R W; Kushmerick, M J (1997) Phosphorus metabolite distribution in skeletal muscle: quantitative bioenergetics using creatine analogs. Mol Cell Biochem 174:23-8 |
| Wiseman, R W; Kushmerick, M J (1995) Creatine kinase equilibration follows solution thermodynamics in skeletal muscle. 31P NMR studies using creatine analogs. J Biol Chem 270:12428-38 |
