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Until corrective genetic strategies overcome several major obstacles, other ways to ameliorate the pathophysiology of muscular dystrophies are required. We used an electroporation-assisted plasmid based gene transfer protocol in tibialis anterior (TA) muscles of mdx dystrophic mice to test the efficacy of over-expressing two proteins that have shown potential for improving the dystrophic pathology. We hypothesized that administration of insulin-like growth factor-I (IGF-I) and Interleukin-15 (IL-15) to muscles of mdx mice would have synergistic effects by simultaneously promoting muscle fibre growth and reducing fibrosis, thereby improving dystrophic muscle function. Mice were anaesthetised with pentobarbital sodium (60 mg/kg, i.p) and the right TA muscle surgically exposed and injected with the appropriate plasmid DNA (or their combination) using a 29 gauge needle, and electroporated (75-100 V/cm). After 4 weeks, the animals were anaesthetised (pentobarbital sodium, 60 mg/kg, i.p.) and muscle function determined in situ. Anaesthetised mice were killed by cardiac excision. Non-viral gene transfer of IGF-I caused skeletal muscle fibre hypertrophy in mdx mice, but did not improve the functional properties of TA muscles. IL-15 delivery had minimal effects on muscle structure or function in mdx mice and did not enhance (or negate) the effects of IGF-I when co-administered. Functional characteristics are critical end-points for assessing the potential of such therapies in dystrophic muscle and our findings highlight the limitations of delivering IGF-I post-natally via plasmid-based gene transfer for improving the dystrophic phenotype and show that IL-15 and IGF-I do not act synergistically in dystrophic skeletal muscle in vivo when delivered this way.