Kisspeptin and gonadotropin-releasing hormone signaling in skeletal muscle

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Chronic inflammation contributes to skeletal muscle atrophy and impaired regenerative capacity. Previous research has identified skeletal muscle inflammatory susceptibility (MuIS), or the ability to manage and respond to inflammation, as a predictor of failed skeletal muscle regeneration and regrowth following surgery. This inflammatory susceptibility is associated with human aging and likely contributes to the adverse structural, metabolic, and functional tissue remodeling that occurs in aged adults. The etiology for heightened inflammation in skeletal muscle is unclear, particularly in healthy young adults. Research that elucidates the mechanisms by which inflammation impairs skeletal muscle regeneration is necessary for identifying potential therapeutic targets. Previous research from our laboratory identified kisspeptin-1 (KISS1) as a highly differentially expressed gene (DEgene) associated with lower inflammatory susceptibility (MuIS-) in human skeletal muscle. When the MuIS- group was compared to a group with an improved hypertrophic response to resistance training, gonadotropin-releasing hormone (GnRH) signaling emerged as a top canonical pathway. In the present study, we aimed to investigate the potential relationship between KISS1/GnRH signaling and inflammation in skeletal muscle and elucidate the relevant signaling pathways. The presence of the GnRH receptor (GnRHr) was assessed in the skeletal muscle of mice genetically modified to constitutively express β-galactosidase at the GnRHr promoter (RG) and wild type (WT) mice using a β-galactosidase gene detection assay. Cell culture experiments using differentiated human muscle progenitor cells (hMPCs) and immortalized mouse skeletal muscle stem cells (C2C12 cells) were performed to determine activation of canonical GnRH signaling (i.e., mitogen-activated protein kinases [MAPKs]), following treatment with Buserelin, a GnRH analog. The National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) datasets were searched for pathological conditions in which KISS1, KISS1 receptor (KISS1r), GnRH, or GnRHr was differentially expressed in skeletal muscle and under inflammatory conditions in other organs. Results were analyzed using the NCBI software GEO2R, which contains R packages from the Bioconductor project. Lastly, the potential relationship between GnRH and inflammatory signaling was assessed using reverse transcription-polymerase chain reaction (RT-PCR) analysis of interleukin 6 (IL-6) following treatment with Buserelin and the inflammatory cytokine tumor necrosis factor alpha (TNF). GnRHr was detected at the protein level in RG but not WT muscle, which validates the presence of GnRHr in skeletal muscle tissue. GnRH signaling may activate extracellular signal-related kinase (ERK) in human skeletal muscle. Additionally, the transcription factor cAMP response element-binding protein (CREB) and Jun N-terminal kinase (JNK) have the capability to respond to Buserelin and Antide treatments in differentiated C2C12 cells. KISS1/GnRH expression was found to be downregulated in several inflammatory myopathies, including juvenile dermomyositis, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, facioscapulohumeral dystrophy, tibial muscular dystrophy, and myotonic dystrophy type 2. GnRH did not impact the acute TNF-mediated increase in IL-6 mRNA levels in skeletal muscle. Our data confirm that GnRHr protein is present and functional in skeletal muscle. Further, our results demonstrate that KISS1/GnRH have a relationship with inflammation that is impacted with inflammatory susceptibility and myopathies with signaling that may occur through the MAPK signaling pathway. Future research should focus on identifying phenotypes associated with a lack of KISS1 or GnRH signaling in skeletal muscle; KISS1/GnRH is a potential therapeutic target to attenuate heightened inflammation in disease states.

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gonadotropin-releasing; kisspeptin; muscle; skeletal; hormone; Inflammation; Endocrinology; Biology; Biochemistry


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Union Local


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Thalacker-Mercer, Anna E.

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Lujan, Marla E.

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M.S., Nutrition

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Master of Science

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dissertation or thesis

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