ACCUMULATION OF MUSCLE ANKYRIN REPEAT PROTEIN TRANSCRIPT REVEALS LOCAL ACTIVATION OF PRIMARY MYOTUBE ENDCOMPARTMENTS DURING MUSCLE MORPHOGENESIS

The characteristic shapes and positions of each individual body muscle are established during the process of muscle morphogenesis in respons e to patterning information from the surrounding mesenchyme, Throughou t muscle morphogenesis, primary myotubes are arranged in small paralle l bundles, each myotube spanning the forming muscles from end to end. This unique arrangement potentially assigns a crucial role to primary myotube end regions for muscle morphogenesis. We have cloned muscle an kyrin repeat protein (MARP) as a gene induced in adult rat skeletal mu scle by denervation. MARP is the rodent homologue of human C-193 (Chu, W., D.K. Burns, R.A. Swerick, and D.H. Presky. 1995. J. Biol. Chem. 2 70:10236-10245) and is identical to rat cardiac ankyrin repeat protein . (Zou, Y., S. Evans, J. Chen, H.-C. Kuo, R.P. Harvey, and K.R. Chien. 1997. Development. 124:793-804). In denervated muscle fibers, MARP tr anscript accumulated in a unique perisynaptic pattern. MARP was also e xpressed in large blood vessels and in cardiac muscle, where it was fu rther induced by cardiac hypertrophy. During embryonic development, MA RP was expressed in forming skeletal muscle. In situ hybridization ana lysis in mouse embryos revealed that MARP transcript exclusively accum ulates at the end regions of primary myotubes during muscle morphogene sis. This closely coincided with the expression of thrombospondin-4 in adjacent prospective tendon mesenchyme, suggesting that these two com partments may constitute a functional unit involved in muscle morphoge nesis. Transfection experiments established that MARP protein accumula tes in the nucleus and that the levels of both MARP mRNA and protein a re controlled by rapid degradation mechanisms characteristic of regula tory early response genes. The results establish the existence of nove l regulatory muscle fiber subcompartments associated with muscle morph ogenesis and denervation and suggest that MARP may be a crucial nuclea r cofactor in local signaling pathways from prospective tendon mesench yme to forming muscle and from activated muscle interstitial cells to denervated muscle fibers.