The effect of metalloendoprotease inhibitors on the biochemical differentiation of the rat skeletal muscle line, L6, was investigated. Confluent unfused L6 cells exposed briefly to 1,10-phenanthroline, a chelator of divalent metal cations, or continuously to dipeptide amide metalloendoprotease substrates that are blocked at the NH2-terminals, N-carbobenzyloxyserylleucyl amide and N-carbobenzyloxyglycylleucyl amide, did not fuse or express creatine kinase, myosin heavy chain, or alpha-actin. These effects were reversible and dose-dependent. Exposure to N-carbobenzyloxylglycylglycyl amide, which is not a metalloendoprotease inhibitor, had no effect. As the differentiation in a culture progressed, 1,10-phenanthroline became less effective in blocking the accumulation of creatine kinase and myosin heavy chain. Exposure of partially fused cultures to N-carbobenzyloxyserylleucyl amide prevented any further accumulation of muscle-specific proteins. In confluent cultures where cell division was blocked before the onset of differentiation, N-carbobenzyloxyserylleucyl amide still prevented fusion and the induction of creatine kinase. This indicates that these inhibitors do not act by interfering with the cell cycle. Experiments that measured DNA synthesis rates, plating efficiencies, and the effects of sequential dipeptide and dimethyl sulfoxide treatments indicate that L6 myoblasts do not irreversibly withdraw from the cell cycle when exposed to N-carbobenzyloxyserylleucyl amide. These results are consistent with the role of a metalloendoprotease in initiating the terminal differentiation of cultured muscle cells.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.