Sepsis Attenuates the Anabolic Response to Skeletal Muscle Contraction

Abstract

Electrically stimulated muscle contraction is a potential clinical therapy to treat sepsis-induced myopathy; however, whether sepsis alters contraction-induced anabolic signaling is unknown. Polymicrobial peritonitis was produced by cecal ligation and puncture (CLP) in male C57BL/6 mice and time-matched, pair-fed controls (CON). At ~24 h post-CLP, the right hindlimb was electrically stimulated via the sciatic nerve to evoke maximal muscle contractions and the gastrocnemius was collected 2 h later. Protein synthesis was increased by muscle contraction in CON mice. Sepsis suppressed the rate of synthesis in both the non-stimulated (31%) and stimulated (57%) muscle versus CON. Contraction of muscle in CON mice increased the phosphorylation of mTORC1 substrates S6K1 Thr389 (8-fold), S6K1 Thr421/Ser424 (7-fold) and 4E-BP1 Ser65 (11-fold). Sepsis blunted the contraction-induced phosphorylation of S6K1 Thr389 (67%), S6K1 Thr421/Ser424 (46%) and 4E-BP1 Ser65 (85%). Conversely, sepsis did not appear to modulate protein elongation as eEF2 Thr56 phosphorylation was decreased similarly by muscle contraction in both groups. MAPK signaling was discordant following muscle contraction in septic muscle; phosphorylation of ERK Thr202/Tyr204 and p38 Thr180/Tyr182 was increased similarly in both CON and CLP mice while sepsis prevented the contraction-induced phosphorylation of JNK Thr183/Tyr185 and c-JUN Ser63. The expression of IL-6 and TNF-α mRNA in muscle was increased by sepsis, and contraction increased TNF-α to a greater extent in muscle from septic than CON mice. Injection of the mTOR inhibitor Torin2 in separate mice confirmed that contraction-induced increases in S6K1 and 4E-BP1 were mTOR-mediated. These findings demonstrate that resistance to contraction-induced anabolic signaling occurs during sepsis and is predominantly mTORC1-dependent.

Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity

“…Experimental design. Polymicrobial peritonitis was induced using CLP, and separate groups of mice were studied in the acute phase of sepsis (i.e., 24 h post-CLP) (54) or during the recovery phase (i.e., 10 days post-CLP) (60). Briefly, mice were anesthetized with isoflurane (3-4% induction with 2-3% maintenance, Vedco, St. Joseph, MO) in 100% O 2.…”

Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle

“…Although previously we have reported that sepsis increases REDD1 (48), the causal contribution of this increase to the reduction in mTORC1 signaling and protein synthesis is unknown. Therefore, mice with a global deletion of REDD1 were used to test the hypothesis that elimination of REDD1 would ameliorate the sepsis-induced inhibition of mTORC1 and thereby antagonize the impairment in protein synthesis and contribute to improved survival.…”

“…Cecal ligation and puncture (CLP) was used to produce sepsis and was performed as described previously (48). Mice were anesthetized (isoflurane, 2-3% in O2 with 1.5% maintenance), and the abdomen was shaved and aseptically prepared.…”

“…rgulated in development and DNA damage-1; mechanistic target of rapamycin complex 1; protein synthesis; autophagy; cecal ligation and puncture; proteolysis; critical illness SKELETAL MUSCLE ATROPHY IS A DEBILITATING CONSEQUENCE of sepsis and critical illness that increases the length of hospitalization and mortality (19). Loss of muscle mass and strength during sepsis results from the prolonged imbalance between rates of protein synthesis and degradation caused by several factors, including increased proinflammatory cytokine signaling, anabolic resistance, and excess glucocorticoids (1,32,48). Protein synthesis is controlled predominantly by the mechanistic (a.k.a.…”

Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism

“…Using cecal ligation and puncture (CLP) as an acute mouse model of sepsis, it was shown that REDD1 protein was increased in the gastrocnemius of male mice along with a decrease in protein synthesis independent of changes in mTORC1 signaling (119). Interestingly, the increase in REDD1 was not offset by a bout of stimulated muscle contractions (ϳ18 h post-sepsis induction and 2 h prior to muscle collection), showing that sepsis rendered REDD1 unresponsive to this significant anabolic stimulus compared with the control condition in which REDD1 protein was reduced by muscle contractions (119).…”