Myogenesis – The Early Years

Over a hundred years has passed between the first publication on skeletal muscle regeneration and when a mechanistic understanding of the biology of regeneration was realized. The reason for the delay is rooted in the pace of change in the technology at hand to investigate this process. While the microscope was invented in the 18th century, the first description of the response of skeletal muscle to injury did not appear until the middle of the 19th century (Waldeyer, 1865). It was believed that muscles basically did not regenerate, however, Waldeyer found that human muscle regenerated in tissue isolated from patients who survived a typhoid epidemic. Several decades earlier Schwann (Schwann, 1839) observed that muscles of embryos were multinucleated and proposed they formed by a process of coalescences, though he probably did not propose cell fusion, but merely aggregation. It became accepted that skeletal muscle was multinucleated and that many nuclei appeared in the region of muscle damage. The question was how could regenerating fiber become nucleated? It was commonly thought for nearly the next 100 years that cytoplasmic buds protruded from the broken ends of fibers to close the gap between damaged fiber ends. But it was difficult to explain the ribbons of nuclei that were so apparent to all that observed the process under the microscope. A number of theories were proposed – that muscle fiber nuclei were extruded from the damage fiber into the buds, that they came from the proliferating cells surrounding the fiber, or that they were from cells that migrated from other sites. Of course, the latter two hypotheses alone could not explain multinucleation of the fibers, although they were prophetic in recognizing some century and a half later that blood borne stem cells could be shown to contribute to the nuclear population of damaged muscle. Left unsettled and a source for much speculation was the mechanism of nucleation. 1