Sepsis attenuates the anabolic response to skeletal muscle contraction

Jennifer L. Steiner, Charles H. Lang

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 nonstimulated (31%) and stimulated (57%) muscle versus CON. Contraction of muscle in CON mice increased the phosphorylation of mTORC1 (mammalian target of rapamycin [mTOR] complex 1) substrates S6K1 (70-kd ribosomal protein S6 kinase 1) 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. Mitogen-activated protein kinase signaling was discordant following contraction in septic muscle; phosphorylation of extracellular signal-regulated kinase 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 interleukin 6 and tumor necrosis factor α (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.

Original languageEnglish (US)
Pages (from-to)344-351
Number of pages8
JournalShock
Volume43
Issue number4
DOIs
StatePublished - Apr 16 2015

Fingerprint

Muscle Contraction
Sepsis
Skeletal Muscle
Phosphorylation
Punctures
Ligation
Muscles
Sirolimus
Tumor Necrosis Factor-alpha
Ribosomal Protein S6 Kinases
Extracellular Signal-Regulated MAP Kinases
Muscular Diseases
Sciatic Nerve
Hindlimb
Mitogen-Activated Protein Kinases
Peritonitis
Inbred C57BL Mouse
Interleukin-6
Proteins
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Steiner, Jennifer L. ; Lang, Charles H. / Sepsis attenuates the anabolic response to skeletal muscle contraction. In: Shock. 2015 ; Vol. 43, No. 4. pp. 344-351.
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Sepsis attenuates the anabolic response to skeletal muscle contraction. / Steiner, Jennifer L.; Lang, Charles H.

In: Shock, Vol. 43, No. 4, 16.04.2015, p. 344-351.

Research output: Contribution to journalArticle

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