Sarcopenia‐related changes in serum GLP‐1 level affect myogenic differentiation

Abstract

AbstractBackgroundSarcopenia, a group of muscle‐related disorders, leads to the gradual decline and weakening of skeletal muscle over time. Recognizing the pivotal role of gastrointestinal conditions in maintaining metabolic homeostasis within skeletal muscle, we hypothesize that the effectiveness of the myogenic programme is influenced by the levels of gastrointestinal hormones in the bloodstream, and this connection is associated with the onset of sarcopenia.MethodsWe first categorized 145 individuals from the Emergency Room of Taipei Veterans General Hospital into sarcopenia and non‐sarcopenia groups, following the criteria established by the Asian Working Group for Sarcopenia. A thorough examination of specific gastrointestinal hormone levels in plasma was conducted to identify the one most closely associated with sarcopenia. Techniques, including immunofluorescence, western blotting, glucose uptake assays, seahorse real‐time cell metabolic analysis, flow cytometry analysis, kinesin‐1 activity assays and qPCR analysis, were applied to investigate its impacts and mechanisms on myogenic differentiation.ResultsIndividuals in the sarcopenia group exhibited elevated plasma levels of glucagon‐like peptide 1 (GLP‐1) at 1021.5 ± 313.5 pg/mL, in contrast to non‐sarcopenic individuals with levels at 351.1 ± 39.0 pg/mL (P < 0.05). Although it is typical for GLP‐1 levels to rise post‐meal and subsequently drop naturally, detecting higher GLP‐1 levels in starving individuals with sarcopenia raised the possibility of GLP‐1 influencing myogenic differentiation in skeletal muscle. Further investigation using a cell model revealed that GLP‐1 (1, 10 and 100 ng/mL) dose‐dependently suppressed the expression of the myogenic marker, impeding myocyte fusion and the formation of polarized myotubes during differentiation. GLP‐1 significantly inhibited the activity of the microtubule motor kinesin‐1, interfering with the translocation of glucose transporter 4 (GLUT4) to the cell membrane and the dispersion of mitochondria. These impairments subsequently led to a reduction in glucose uptake to 0.81 ± 0.04 fold (P < 0.01) and mitochondrial adenosine triphosphate (ATP) production from 25.24 ± 1.57 pmol/min to 18.83 ± 1.11 pmol/min (P < 0.05). Continuous exposure to GLP‐1, even under insulin induction, attenuated the elevated glucose uptake.ConclusionsThe elevated GLP‐1 levels observed in individuals with sarcopenia are associated with a reduction in myogenic differentiation. The impact of GLP‐1 on both the membrane translocation of GLUT4 and the dispersion of mitochondria significantly hinders glucose uptake and the production of mitochondrial ATP necessary for the myogenic programme. These findings point us towards strategies to establish the muscle–gut axis, particularly in the context of sarcopenia. Additionally, these results present the potential of identifying relevant diagnostic biomarkers.