Liver kinase B1 inhibits the expression of inflammation-related genes postcontraction in skeletal muscle

Abstract

Skeletal muscle-specific liver kinase B1 (LKB1) knockout mice (skmLKB1-KO) exhibit elevated mitogen-activated protein kinase (MAPK) signaling after treadmill running. MAPK activation is also associated with inflammation-related signaling in skeletal muscle. Since exercise can induce muscle damage, and inflammation is a response triggered by damaged tissue, we therefore hypothesized that LKB1 plays an important role in dampening the inflammatory response to muscle contraction, and that this may be due in part to increased susceptibility to muscle damage with contractions in LKB1-deficient muscle. Here we studied the inflammatory response and muscle damage with in situ muscle contraction or downhill running. After in situ muscle contractions, the phosphorylation of both NF-κB and STAT3 was increased more in skmLKB1-KO vs. wild-type (WT) muscles. Analysis of gene expression via microarray and RT-PCR shows that expression of many inflammation-related genes increased after contraction only in skmLKB1-KO muscles. This was associated with mild skeletal muscle fiber membrane damage in skmLKB1-KO muscles. Gene markers of oxidative stress were also elevated in skmLKB1-KO muscles after contraction. Using the downhill running model, we observed significantly more muscle damage after running in skmLKB1-KO mice, and this was associated with greater phosphorylation of both Jnk and STAT3 and increased expression of SOCS3 and Fos. In conclusion, we have shown that the lack of LKB1 in skeletal muscle leads to an increased inflammatory state in skeletal muscle that is exacerbated by muscle contraction. Increased susceptibility of the muscle to damage may underlie part of this response.

LKB1/p53/TIGAR/autophagy-dependent VEGF expression contributes to PM2.5-induced pulmonary inflammatory responses

“…It can not only exert the protective functions in antagonizing the inflammatory responses induced by mycobacterial infection, LPS or FGF21 24,27,29 , but also play critical roles in controlling the inflammation in T cells, cardiomyocyte, renal epithelial cilia, brown adipose tissue, skeleton muscle, etc. 25,26,28,30,31 . In the current study, we have provided the novel evidence that LKB1 was involved in mediating the proinflammatory responses in the bronchial epithelial cells upon PM2.5 exposure.…”

Resveratrol prevents sarcopenic obesity by reversing mitochondrial dysfunction and oxidative stress via the PKA/LKB1/AMPK pathway

“…Moreover, previous investigations have demonstrated that AMPK activity is reduced in skeletal muscle tissues of high-fat diet (HFD)-fed rats [17,18]. Liver kinase B1 (LKB1), a major upstream AMPK kinase, has been shown to promote mitochondrial biogenesis and antioxidative pathways in skeletal muscle after its activation [19–21]. Protein kinase A (PKA), an upstream kinase in the LKB1/AMPK pathway [22], has been identified as a potential target for muscle wasting in several conditions [23].…”

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

“…Recently, several reports have identified increased inflammatory signaling upon Lkb1 loss in different cell and tissue contexts, such as in skeletal muscle (12), macrophages (13), T cells (14), and lung cancer (15), implicating Lkb1 as a suppressor of inflammatory pathways. In PJS patients and in Lkb1 +/-mice, inhibition of cyclooxygenase-2 with the selective inhibitor celecoxib demonstrated partial efficiency in reducing PJS polyposis by reducing the size but not the number of tumors (16).…”