Muscle hypertrophy induced by the Ski protein: cyto-architecture and ultrastructure

Aim: Transgenic mice overexpressing the c-ski proto-oncogene driven by the MSV promoter undergo muscle hypertrophy, most notably fast fibres of the lower limb. This hypertrophy is not accompanied by a correspondingly large increase in force, and individual skinned muscle fibres exhibit a 30% reduction in force per cross-sectional area. In this respect, the MSV ski model is different from most other hypertrophy models and we here aim at describing the mechanisms for the reduced specific force. Methods: Cyoarchitecture and ultrastructure of muscle fibres from the fast extensor digitorum longus muscle of 2-3 months old MSV ski mice was studied. In addition to electron microscopy, we used in vivo intracellular injections of myonuclear dye to investigate nuclear number. Results: The number of nuclei did not increase in proportion to size, and consequently nuclear domains were increased compared with wild type. The fraction of the cytoplasm occupied by contractile material was reduced by 18%. In addition we observed poor intracellular alignment of Z-discs. Such staggering has been reported to reduce force in desmin deficient mice, but the amount and distribution of desmin in the MSV ski mice seemed normal. The mitochondria of MSV ski mice showed irregularly spaced cristae that were frequently disrupted. Conclusion: The reduction in specific force observed in MSV ski mice could be explained by a reduced fraction of contractile material and reduced transversal mechanical coupling. The ultrastructural abnormalities could be related to an increase in nuclear domains.