Protective Effects of Glutamine and Leucine Supplementation on Sepsis-Induced Skeletal Muscle Injuries

Abstract

This study investigated the effects of l-glutamine (Gln) and/or l-leucine (Leu) administration on sepsis-induced skeletal muscle injuries. C57BL/6J mice were subjected to cecal ligation and puncture to induce polymicrobial sepsis and then given an intraperitoneal injection of Gln, Leu, or Gln plus Leu beginning at 1 h after the operation with re-injections every 24 h. All mice were sacrificed on either day 1 or day 4 after the operation. Blood and muscles were collected for analysis of inflammation and oxidative damage-related biomolecules. Results indicated that both Gln and Leu supplementation alleviated sepsis-induced skeletal muscle damage by reducing monocyte infiltration, calpain activity, and mRNA expression levels of inflammatory cytokines and hypoxia-inducible factor-1α. Furthermore, septic mice treated with Gln had higher percentages of blood anti-inflammatory monocytes and muscle M2 macrophages, whereas Leu treatment enhanced the muscle expressions of mitochondrion-related genes. However, there were no synergistic effects when Gln and Leu were simultaneously administered. These findings suggest that both Gln and Leu had prominent abilities to attenuate inflammation and degradation of skeletal muscles in the early and/or late phases of sepsis. Moreover, Gln promoted the switch of leukocytes toward an anti-inflammatory phenotype, while Leu treatment maintained muscle bioenergetic function.

Role of Glucocorticoid Signaling and HDAC4 Activation in Diaphragm and Gastrocnemius Proteolytic Activity in Septic Rats

“…In contrast, a progressive decrease in both muscle mass and the fiber cross-sectional area during seven days after sepsis induction has been observed in limb muscles [ 4 , 6 , 7 ]. There are several factors that can mediate sepsis-induced muscle wasting, muscle inflammation, increased autophagy, upregulation of the ubiquitin-proteasome system, and increased calpain activity and mitochondria dysfunction [ 6 , 7 , 12 , 13 ]. All these factors are induced by sepsis in both the diaphragm and limb muscles, but these responses in the diaphragm are smaller and transient in comparison with those of limb muscles, which are stronger and prolonged [ 6 , 7 ].…”

Branched‐Chain Amino Acids and Mitochondrial Biogenesis: An Overview and Mechanistic Summary

“…[ 69 ] In septic mice, injection with leucine (1 g kg −1 ) increased muscle mRNA expression of Ppargc1a after 4 days (but not 1 day) of treatment. [ 70 ] And similar to their findings in an in vitro model of muscle, Institute of Cancer Research (ICR) mice supplemented with leucine at 500 mg kg −1 day −1 showed increased expression of mitochondrial biogenic‐related targets (pAMPK, PGC‐1α, NRF1, and TFAM expression, with unchanged SIRT1 expression) in quadriceps femoris muscle. [ 58 ] Leucine supplementation at 135 mg kg −1 BW for 1–3 h also increased mitochondrial biogenic signaling in male Wistar rats, evidenced by increased expression of Ppargc1a , Tfam , Atp5o , and Cycs in EDL, and increased Ppargc1a in soleus, which were harvested 3 h post gavage.…”

“…In addition to in vitro data supporting a role for BCAA in mitochondrial biogenic signaling, several reports have also investigated the effects of individual or combination BCAA treatments on mitochondrial biogenesis and function in vivo. While valine and isoleucine are currently under‐investigated, leucine treatment has repeatedly resulted in increased mitochondrial biogenic signaling [ 22 , 30 , 31 , 58 , 68 , 69 , 70 , 71 , 72 , 73 ] and/or function [ 68 , 72 ] in several experimental models, such as male B6.Cg‐Ay/J mouse soleus, [ 68 ] aged C57BL/6J mouse quadriceps, [ 69 ] septic C57BL/6J mouse gastrocnemius, [ 70 ] ICR mouse quadriceps femoris, [ 58 ] C57BL/6J mouse WAT, [ 71 ] male Wistar rat soleus, [ 22 ] male Wistar rat EDL, [ 22 ] piglet Longissimus dorsi , [ 31 , 72 ] piglet liver, [ 30 ] and NW and growth‐slowed piglet liver. [ 73 ] For example, 1.5% leucine in drinking water for 4 months has been shown to increase expression levels of Ppara , Ucp3 , and Nrf1 in soleus muscle of Ay mice, as well as increase total energy expenditure (VO 2 ).…”

Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

“…Furthermore, downregulation of α-ketoglutarate is controlled by isocitrate dehydrogenase (IDH), which is a downstream target of the nuclear receptor Nur77 ( Nr4a1 ) [ 235 ]. Therefore, glutamine promotes anti-inflammatory functions of macrophages through Nur77-mediated transcription [ 236 , 237 ]. Additional functions of glutamine in macrophages include promoting phagocytosis as metabolism of glutamine through glutaminase-1 is essential for macrophages to eliminate apoptotic cells [ 238 ].…”