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%u010ceskoslovensk%u00e1 fyziologie 73/2025 %u010d. 2 33P%u0158EHLEDN%u00c9 %u010cL%u00c1NKYreticulum (ER) stress, enhancing mitochondrial function, and improving lipid and glucose metabolism; further highlighting the dynamic relationship between skeletal muscle and liver (van der Windt et al., 2018). Additional advancement in the therapeutic approach to MASLD relies on the proper comprehension of its intricate pathophysiological processes and how each step could be halted. This may include, targeting defective mitochondrial genes (Chen et al., 2023), managing oxidative stress (Delli Bovi et al., 2021), and tackling metabolic disturbances such as insulin resistance and T2DM. THE PATHOPHYSIOLOGICAL PATHWAYS IN MASLD AND ITS CONNECTION WITH SKELETAL MUSCLEInsulin resistance and type 2 diabetes in MASLD There is a complex and significant connection between insulin resistance, T2DM, and MASLD (Ziolkowska et al., 2021). Insulin resistance is an integral component of MASLD, playing a vital role in its pathogenesis and aggravation. Additionally, skeletal muscle dysfunction further exacerbates the metabolic pathologies associated with MASLD (Veskovi%u0107 et al., 2023). Insulin is responsible for promoting glucose uptake and lipid storage, both of which are affected in the case of insulin resistance (Ziolkowska et al., 2021). Given that the liver serves as a main regulator for glucose and lipid metabolism it is the predominantly affected organ. Consequently, as hepatic insulin resistance advances, the liver undergoes increased lipogenesis and decreased fatty acid oxidation leading to hepatic steatosis (Padda et al., 2021). Skeletal muscle is another tissue that plays a key role in the physiological metabolic processes of glucose and lipids (Morales et al., 2017) and is therefore also severely impacted by insulin resistance (Merz & Thurmond, 2020). Insulin is the primary hormone responsible for skeletal muscle uptake and utilization of glucose, thus as resistance to insulin increases, aggravation of hyperglycaemia is the inevitable result (Abdul-Ghani & DeFronzo, 2010). Myosteatosis %u2013 fat accumulation within muscle cells %u2013 is usually present in patients with metabolic disturbances, which further worsens the sensitivity of muscle tissue to insulin. As the disease progresses, the utilization of carbohydrates and lipids as energy substrates deteriorates. Consequently, glycogen stores in the liver become depleted, causing the body to utilize proteins instead which ultimately elicits pronounced protein breakdown (Fujita et al., 2006). Increased protein catabolism from muscle tissue results in an overall reduced skeletal muscle mass (Zhao, Yin & Deng, 2023).Inflammation and oxidative stressInflammation and oxidative stress are other cardinal contributors to liver pathology in MASLD by both directly impacting the liver tissue as well as indirectly through other organ dysfunction, such as skeletal muscle tissue dysfunction. The %u201ctwo-hit%u201d hypothesis of the pathogenesis of MASLD states that the first hit affecting the liver is the insulin resistance that causes hepatic lipid accumulation followed by a second hit which is represented by oxidative stress and inflammation. An updated term of %u201cmultiple parallel hits%u201d has recently been recognized. This term encompasses a broader range of factors, including hormonal imbalance, intestinal microflora dysregulation and environmental triggers which all act together to exacerbate MASLD and its systemic consequences (Delli Bovi et al., 2021). Oxidative stress in MASLD occurs when lipids excessively accumulate in hepatocytes, successively triggering the activation of inflammatory pathways, including pro-inflammatory cytokines such as TNF-alpha, Interleukin-6, and C reactive protein (CRP) (Arroyave-Ospina et al., 2021). This eventually leads to hepatitis and later generalized systemic inflammation. The systemic inflammatory state promotes a chain of metabolic dysfunctions that goes beyond the liver to include the gastrointestinal tract and skeletal muscle via promoting insulin resistance and reducing glucose uptake (Li & Wang, 2020).Skeletal muscle tissue is also directly affected due to its high oxygen consumption. Oxidative stress affects the physiological balance of mitochondrial protein response and phagocytosis, which is important for maintaining muscle health and function. Cytokines, especially TNF-alpha, not only yield reactive oxygen species (ROS) and oxidative stress in cells but also directly induce muscular proteolysis (Chen et al., 2023). Oxidative stress is a predisposing factor for muscle fibrosis due to excessive extracellular matrix production. This subsequently leads to diminished muscular functions including the basic movement and force generation. Not only muscular fibrosis halts normal movement, but also reduces the proliferation of the satellite cells impeding muscular regeneration (Gonzalez et al., 2020). Signalling modulatorsIn MASLD, the hepatic tissue and skeletal muscles crosstalk in a complex way that involves various signalling molecules. This reciprocal communication is induced through muscle-derived cytokines %u201cmyokines%u201d and liver-derived cytokines %u201chepatokines%u201d. These signals affect metabolism, inflammation, and alter insulin sensitivity in both tissues (Miao et al., 2024; Severinsen & Pedersen, 2020). Myokines such as irisin, myostatin, and interleukin 6 (IL-6) are all secreted by skeletal muscles during physical activity and directly influence hepatic function. Ongoing research of these signalling modulators helps provide profound insight into understanding MASLD and its systemic consequences. MyokinesIrisin, is a newly discovered myokine that has beneficial endocrinological and metabolic functions. Irisin is described as an exercise- mediated myokine that increases during and after exercise (Bostr%u00f6m et al., 2012). A significant function of irisin includes thermogenesis, providing white adipose tissue with thermogenic function like brown adipose tissue (Bostr%u00f6m et al., 2012). Irisin also plays a role in glucose homeostasis, particularly by promoting muscular glycogen synthesis and glucose uptake via GLUT4, thus improving insulin sensitivity (Yano et al., 2021). It additionally promotes glycogen formation by activating the liver glycogen synthase through the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and reduces gluconeogenesis by downregulating the