Apoptosis-related proteins in skeletal muscle fibers of spinal muscular atrophy.

There is evidence that apoptosis in spinal muscular atrophies (SMA) is not restricted to motor neurons but also affects muscle fibers. Studying the expression of several apoptosis-associated proteins we found constant expression of bax in muscle fibers, which promoted cell death. The expression of bax correlated with defective innervation of muscle fibers was also indicated by upregulation of N-CAM. While in early-onset SMA atrophic as well as normo- and hypertrophic muscle fibers displayed expression of bax, muscle fibers in late-onset SMA and peripheral neuropathies showed bax-expression only in atrophic fibers. Other investigated apoptosis-associated factors comprised interleukin-1 beta converting enzyme (ICE), mediating cell death by cleavage of actin filaments, as well as bcl-2 and bcl-x, both inhibiting apoptosis by acting as antioxidants. They were only expressed in atrophic muscle fibers, predominantly in late-onset SMA and peripheral neuropathies. We consider the lack of expression of these apoptosis-related proteins in early infantile SMA to be associated with muscle fiber immaturity due to defective innervation and suggest that immature muscle fibers are not able to produce sufficient levels of some proteins. A sufficient amount of expression of apoptosis-protecting factors such as bcl-2 is needed to neutralize high bax-levels, and a lack of this expression will secondarily promote muscle fiber death in defective innervation.