Pentoxifylline improves insulin action limiting skeletal muscle catabolism after infection

Abstract

We investigated the ability of pentoxifylline (PTX) to modulate protein synthesis and degradation in the presence and absence of insulin during incubation of epitrochlearis muscle, 2 or 6 days after injection of Escherichia coli. On days 2 and 6 after infection, protein synthesis was inhibited by 25%, whereas proteolysis was enhanced by 75%. Insulin (2 nM) in vitro stimulated protein synthesis in muscles from infected rats to the same extent as in controls. The ability of insulin to limit protein degradation was severely blunted 48 h after infection. On day 6 after infection, insulin inhibited proteolysis to a greater extent than on day 2. PTX suppressed the increase in plasma concentrations of tumor necrosis factor more than 600-fold after injection of bacteria, and partially prevented the inhibition of protein synthesis and stimulation of protein degradation during sepsis. Moreover, PTX administration maintained the responsiveness of protein degradation to insulin during sepsis. Thus cytokines may influence skeletal muscle protein metabolism during sepsis, both indirectly through inhibition of the effects of insulin on proteolysis, and directly on the protein synthesis and degradation machinery.

Phosphorylation of eukaryotic initiation factor eIF2Bε in skeletal muscle during sepsis

“…Administration of TNFbp reduced phosphorylation of eIF2B⑀ in gastrocnemius of septic rats. Thus the reduction in the phosphorylation of eIF2B⑀ correlates with our previous observation that attenuating the TNF response to infection prevents the sepsis-induced inhibition in protein synthesis (1,14,42). In addition, administration of TNFbp to septic rats increased the phosphorylation state of GSK-3, suggesting that TNF may be modifying the phosphorylation state of GSK-3.…”

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I

“…This hypothesis is suggested by recent observations showing that IL-6 is able to inhibit basal IGF-I expression in vitro (Lelbach et al 2001) and to stimulate gene expression of SOCS-3 which exerts a negative feed-back loop controlling GH action (Ram & Waxman 1999, Colson et al 2000. Previous studies documented that muscle proteolysis induced by E. coli injection in rats is reduced by pentoxifylline pretreatment (Vary et al 1999). Our data indicate that this anti-catabolic effect of pentoxifylline does not result from the prevention of the decline of circulating IGF-I.…”

Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle

“…TNF-␣ influences both muscle protein synthesis and degradation (58). TNF-␣ blockade prevents muscle protein breakdown by suppressing the activation of the ubiquitinproteasome-dependent proteolysis in cancer and septic rats (11,37,58).…”

“…Among these, two are increased during skeletal muscle atrophy [muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) or Atrogin-1 (5, 23)]. The gene expressions of these E3 ubiquitin ligases in the skeletal muscle are upregulated in several types of cachexia, including sepsis (33,58). Therefore, it has been proposed that mRNA for these E3 ubiquitin-ligating enzymes are the most sensitive markers for muscular atrophy.…”