Abstract:
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Skeletal muscle weakness and fatigue disorders affect millions of individuals each year and few treatments are available. A high content physiological drug screening technology was developed using skeletal muscle myoblasts bioengineered into contractile muscle tissue to determine the effects of compounds on maximal tetanic force, the rate of muscle fatigue, and contraction-induced muscle damage. The automated system (MyoForce Analysis System, MFASTM) uses 96 microwell plates and determines the cumulative effects of a compound on muscle function over days to weeks. Screening compound banks of clinically approved drugs using normal and dystrophic rodent bioengineered muscle tissue, as well as human normal and dystrophic tissue, identified the biguanide class of compounds as potential attenuators of muscle weakness and fatigue. The anti-hyperglycemic biguanides metformin, phenformin and buformin, as well as the anti-malarial biguanide proguanil, were all active in stimulating maximal tetanic force and reducing the rate of muscle fatigue at concentrations (EC50's from 0.5 to 42 nM) well below those found in the blood of patients taking the drugs for their approved uses. Biguanides are a complex class of compounds widely used as anti-microbial agents, anti-malarial drugs, and anti-hyperglycemic compounds. Thus, while the pathways responsible for the biguanide compounds' effects on skeletal muscle strength and fatigue are unknown, many could move quickly into clinical trials because of their already well-established safety and toxicity record in humans. Low doses of biguanides may therefore be useful in reducing muscle weakness and fatigue in numerous disorders including cancer cachexia, congestive heart failure, chronic obstructive pulmonary disease, sarcopenia, and the muscular dystrophies.
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