Objective: In our rodent models of skeletal muscle adaptation in response to loading exercise, we discovered that nuclear architecture and nuclear position change significantly during normal neonatal development, during compensatory hypertrophy-induced adaptation from fast to slow fiber type, and upon loss of weight-bearing. These changes include alterations in nuclear volume, cytoplasmic volume per nucleus, nuclear shape, and nuclear positioning within the fiber. Nuclear architecture is linked to both the normal and pathologic control of gene expression, through mechanisms that are not yet understood. The emerging concept is that fundamental activities including DNA synthesis, chromatin organization and gene expression, all depend on the interior ultrastructure of the nucleus, particularly the nuclear lamina and a growing number of lamin-associated proteins. Furthermore, mutations in nuclear lamins and lamin-binding proteins cause inherited diseases that affect both skeletal and cardiac muscle. Our results clearly demonstrate that the adaptation of muscle fibers to the fast or slow phenotypes involves specific and characteristic changes in gene expression and in nuclear size, nuclear shape, and nuclear positioning within the cell.
Design: Experimental
Population: Female adult Wistar rats, 120 days old.
Variables: Soleus and Plantaris muscle morphometry and ultratructure. Gel electrophoesis of proteins (Myosin heavy chains, tubulin, kinesin, dynein, titin), Western Blot analysis, and confocal microscopy of immunofluoresently labeled nuclei.
Findings: The results show that we can induce the same characteristic changes in nuclear position, microtubule motor expression and nuclear volume in adult rat muscles, by the hypertrophy-induced adaptation from fast to slow-twitch fiber phenotypes. Myonucleus staining and determination of myonuclei numbers. Following synergist ablation, there was a dramatic visual difference between fiber types. In fast fibers nuclei were disorganized but in slow fibers, nuclei were arranged in longitudinal rows.
Microtubules form by the polymerization of tubulin heterodimers, which consist of two closely-related 55 kD proteins named a- and b-tubulin. During early recovery of SOL muscle from atrophy, we found that the expression of tubulin increased. Single fibers from SOL and PLN muscles during recovery were analyzed for tubulin content by Western blots. Pilot data show that a- and b-tubulin levels significantly increase during the first 14 days of reloaded recovery after 14 days of atrophy, in comparison to control values. We saw similar results in growing neonatal rat pups.
Conclusions :Tubulin levels increase during adaptation from fast or intermediate to slow fibers. We hypothesize that the linear arrangement of nuclei may facilitate inter-nuclear communications required to regulate or coordination protein expression along the full length of the muscle fiber. We propose that increased tubulin expression might be required for nuclear migration events in these muscle fibers.
Implications: If nuclear migration events are required for skeletal muscle to adapt during physical activity and programmed exercise, then pharmocologic agents which alter microtubule structure, such as Taxol or Colchicine may prevent adaptation of skeletal muscle and/or induce serious damage to muscle structure.
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