Molecular modulators of skeletal muscle metabolism in exercise and type 2 diabetes

<p dir="ltr">Skeletal muscle is central to glucose homeostasis and accounts for most postprandial glucose disposal. It has a remarkable metabolic adaptability, especially in response to diet and exercise. Defects in skeletal muscle insulin sensitivity is a major driver of type 2 diabetes mellitus (T2DM). This thesis investigates molecular aspects of skeletal muscle metabolism in health and disease, with a focus on small molecules that may mediate the beneficial effects of exercise or serve as therapeutic modulators in T2DM.</p><p dir="ltr">In study I, we conducted a comparative transcriptomic and functional analysis of three commonly used skeletal muscle cell models: primary human skeletal muscle cells, mouse C2C12, and rat L6 myotubes. This revealed several model-specific differences in response to insulin, substrate oxidation, and gene expression patterns relevant to glucose handling and contractile function. The study can be used as a companion for selecting the most appropriate cell models for studying different aspects of muscle metabolism.</p><p dir="ltr">Study II examined the metabolic effects of glutamine in skeletal muscle using human cohorts, rodent models, and cell cultures. In humans, circulating glutamine levels negatively correlated with body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA- IR). In mice with diet-induced obesity and insulin resistance, glutamine supplementation modulated insulin signalling and reduced markers of obesity-associated skeletal muscle inflammation.</p><p dir="ltr">In study III, we investigated the expression and function of the succinate receptor SUCNR1 (GPR91) in human skeletal muscle. By integrating bulk transcriptomics, single-cell analyses, in situ visualization, and signalling assays, we found SUCNR1 expression to be confined to non- muscle cells; primarily macrophages and smooth muscle cells, within muscle tissue.</p><p dir="ltr">Study IV explored a novel metabolic role for thromboxane signalling in skeletal muscle. Using human plasma metabolomics, murine models, and in vitro experiments, we identified exercise-associated modulation of circulating thromboxane levels and demonstrated that thromboxane receptor activation influences glucose uptake, glycogen synthesis, and systemic glucose tolerance, partly via PKA/filamin A signalling.</p><p dir="ltr">These studies broaden our understanding of skeletal muscle metabolism by revealing novel mechanisms, identifying new signalling pathways, and highlighting the challenges of translating mechanistic insights from model systems to human physiology.</p><h3>List of scientific papers</h3><p dir="ltr">I. Comparative profiling of skeletal muscle models reveals heterogeneity of transcriptome and metabolism. <b>Abdelmoez AM</b>, Sardón Puig L, Smith JAB, Gabriel BM, Savikj M, Dollet L, Chibalin AV, Krook A, Zierath JR, Pillon NJ. Am J Physiol Cell Physiol. 2020 Mar 1;318(3):C615-C626. <a href="https://doi.org/10.1152/ajpcell.00540.2019" rel="noreferrer" target="_blank">https://doi.org/10.1152/ajpcell.00540.2019</a></p><p dir="ltr">II. Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes. Dollet L, Kuefner M, Caria E, Rizo-Roca D, Pendergrast L, <b>Abdelmoez AM</b>, Karlsson HKR, Björnholm M, Dalbram E, Treebak JT, Harada J, Näslund E, Ryden M, Zierath JR, Pillon NJ, Krook A. Diabetes. 2022 Apr 1;71(4):624-636. <a href="https://doi.org/10.2337/db20-0814" rel="noreferrer" target="_blank">https://doi.org/10.2337/db20-0814</a></p><p dir="ltr">III. Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle.<b> </b><b>Abdelmoez AM</b>, Dmytriyeva O, Zurke YX, Trauelsen M, Marica AA, Savikj M, Smith JAB, Monaco C, Schwartz TW, Krook A, Pillon NJ. Am J Physiol Endocrinol Metab. 2023 Apr 1;324(4):E289-E298. <a href="https://doi.org/10.1152/ajpendo.00009.2023" rel="noreferrer" target="_blank">https://doi.org/10.1152/ajpendo.00009.2023</a></p><p dir="ltr">IV. Thromboxane receptor stimulation improves glucose uptake in skeletal muscle cells and whole-body glycaemic control. <b>Abdelmoez AM</b>, Yu X, Rizo-Roca D, Jollet M, Marica AA, Dollet L, Borg M, Björnholm M, Checa A, Olsson T, Otten J, Zierath J, Krook A, Schwartz T, Chibalin AV, Pillon N. [Manuscript]</p>