Context‐dependent functional substitution of α‐skeletal actin by γ‐cytoplasmic actin

We generated transgenic mice that overexpressed γ‐cyto actin 2000‐fold above wild‐type levels in skeletal muscle. 7‐ cyto actin comprised 40% of total actin in transgenic skeletal muscle, with a concomitant 40% decrease in α‐actin. Surprisingly, transgenic muscle was histologically and ultrastructurally identical to wild‐type muscle despite near‐stoichiometric incorporation of γ– cyto actin into sarcomeric thin filaments. Furthermore, several parameters of muscle physiological performance in the transgenic animals were not different from wild type. Given these surprising results, we tested whether overexpression of γ‐ cyto actin could rescue the early postnatal lethality in α‐ sk actin‐null mice (Acta1 –/– ). By quantitative Western blot analysis, we found total actin levels were decreased by 35% in Actal –/– muscle. Although transgenic overexpression of γ‐ cyto actin on the Actal /_ background restored total actin levels to wild type, resulting in thin filaments composed of 60% γ‐ cyto actin and a 40% mixture of cardiac and vascular actin, the life span of transgenic Actal –/– mice was not extended. These results indicate that sarcomeric thin filaments can accommodate substantial incorporation of γ‐ cyto actin without functional consequences, yet γ‐ cyto actin cannot fully substitute for α‐ sk actin.—Jaeger, M. A., Sonnemann, K. J., Fitzsimons, D. P., Prins, K. W., Ervasti, J. M. Contextdependent functional substitution of a‐skeletal actin by y‐cytoplasmic actin. FASEB J. 23, 2205–2214 (2009)