Cell death and apoptosis-related proteins in muscle biopsies of sporadic amyotrophic lateral sclerosis and polyneuropathy

To investigate disease-related differences of cell death and apoptosis in h uman denervation atrophy, we studied DNA fragmentation by the terminal deox ynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) meth od in 38 biopsies of clinically nonaffected and affected muscles from patie nts with sporadic amyotrophic lateral sclerosis (sALS), in 13 muscle biopsi es from patients with chronic peripheral neuropathies, and in 8 biopsies fr om control subjects. In addition, expression of apoptosis-related proteins, bax, bcl-2, and Fas, was studied in 20 biopsies of sALS and 10 chronic per ipheral neuropathies. We identified DNA cleavage in 10% of myofibers of pat ients and in up to 1.5% of control samples. in clinically affected muscles of ALS, a larger amount of TUNEL-positive myofibers (mean 10.5 +/- 5.9%) wa s detected, similar to chronic peripheral neuropathies (mean 10.0 +/- 7.4%) . Atrophic myofibers were immunopositive for bax, bcl-2, and, to a weaker e xtent, for Fas. However, bax-, bcl-2-, or Fas-positive atrophic myofibers d id not reveal consecutive DNA cleavage. Differences between sALS subgroups and chronic peripheral neuropathies were not found. In human denervation at rophy the bcl-2/bax acid the FasL/Fas systems are apparently active indepen dently of DNA fragmentation and apoptosis. DNA fragmentation thus displays an additional reaction that is not disease-specific at chronic stages of hu man denervation processes, probably recapitulating events like skeletal mus cle fiber remodeling in embryonic skeletal tissue development. (C) 2001 Joh n Wiley & Sons.