Skeletal Muscle Health in Metabolic Diseases E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Lebensstil
- Sprache: Englisch
Skeletal Muscle Health in Metabolic Diseases explores the vital role of skeletal muscle in regulating energy metabolism and its interactions with other organs, such as the liver and brain, in the context of metabolic diseases like obesity, diabetes, and fatty liver disease. This comprehensive guide covers how metabolic disorders impact muscle glucose metabolism, liver function, and brain health, alongside the effects of nutrition and exercise on carbohydrate metabolism. Readers will gain insights into the mechanisms underlying muscle atrophy, oxidative stress, and cellular damage caused by these conditions.
Key Features:
- In-depth analysis of skeletal muscle’s role in whole-body metabolism and metabolic disease.
- Exploration of metabolic dysfunction in relation to liver and brain health.
- Insight into the impact of diet and physical activity on muscle and carbohydrate metabolism.
- Examination of muscle atrophy and cellular changes in metabolic disorders.
Readership:
Ideal for students, researchers, and professionals in biomedical and metabolic sciences.
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Seitenzahl: 177
Veröffentlichungsjahr: 2024
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PREFACE
Hiroaki Eshima1Metabolic diseases such as obesity and diabetes cause disruption of systemic energy metabolism and are major public health problems, affecting at least 2 billion people worldwide. The energy metabolism of the whole body is mainly regulated by skeletal muscle, liver, and brain. This book, entitled “Skeletal Muscle Health in Metabolic Disease”, aims to clarify organ and tissue alterations in metabolic diseases, such as obesity, diabetes, and fatty liver.
The book comprises six chapters. The first chapter gives a background of metabolic diseases that affect cellular mechanisms in muscle cells and muscle tissue, especially glucose metabolism in skeletal muscle.
The skeletal muscle and liver share functions as metabolic organs, contributing to systemic metabolic regulation through mutual cooperation. The second chapter discusses the latest findings on the crosstalk between metabolic dysfunction-associated steatotic liver disease (MASLD) and skeletal muscles, which starts and progresses in association with obesity and its associated systemic metabolic abnormalities.
The third chapter focuses on nutrition, especially carbohydrate metabolism. Lipids are stored in the body mainly in the form of triglycerides, whereas carbohydrates are primarily stored in the liver and skeletal muscles in the form of glycogen. Glycogen utilization has also been shown to increase during exercise. When glycogen is depleted, exercise performance is impaired. Therefore, carbohydrate metabolism is important for exercise and the maintenance of organ and tissue homeostasis.
Metabolic diseases are closely associated with brain health and noncommunicable diseases, including type 2 diabetes. By contrast, exercise exerts its beneficial effects on the brain by releasing bioactive substances. The fourth chapter presents how metabolic diseases affect brain health and how exercise mitigates these detrimental effects, focusing particularly on the molecular mechanisms in the brain.
The subsequent five and six chapters discuss muscle atrophy and weakness and cellular mechanisms in metabolic disease. Muscle oxidative stress has been implicated in lipid species composition in the development of type 2 diabetes. Therefore, the sixth chapter discusses the impact of metabolic disorders, such as obesity and type 2 diabetes, on the regulation of lipid species and oxidative stress.
List of Contributors
Muscle Glucose Metabolism in Metabolic Diseases
Hiroaki Eshima1,*Abstract
Metabolic diseases such as obesity and diabetes cause disruption of systemic energy metabolism and are major public health problems, with at least 2 billion people affected worldwide. Skeletal muscle tissue makes a substantial contribution to promoting energy efficiency because it remodels cellular size, composition, and function in response to various nutritional changes. However, metabolic diseases such as impaired insulin sensitivity can dynamically affect the metabolism of skeletal muscle. A deeper understanding of myopathology in metabolic disorders may provide clues for therapeutic strategies to promote skeletal muscle health and improve the overall quality of life. This chapter presents how metabolic diseases via cellular mechanisms affect muscle cells and muscle tissue, especially glucose metabolism in skeletal muscle.
INTRODUCTION
Diabetes and obesity have a high risk of leading to diseases, including myocardial infarction and stroke, which affect life expectancy, and thus therapeutic strategies are needed [1]. A major feature of metabolic disease is insulin resistance. Insulin resistance is associated with obesity and type 2 diabetes mellitus (T2DM). It is generally defined as a reduction in the ability of the body to absorb blood glucose from circulation in response to insulin. Glucose is the main nutrition for energy consumption, but excess blood glucose is an index for obesity and T2DM. Insulin resistance from skeletal muscle is commonly viewed as the critical component of whole-body insulin resistance because the muscle is the most important tissue for insulin-stimulated glucose disposal [2].
Carbohydrates, lipids, and proteins all ultimately break down into glucose and then serve as the primary metabolic fuel in a mammalian cell. Glycogen in skel-
etal muscles contains approximately as much as 50,000 glucose moeties. However, the large increase in muscle glycogen is generally associated with insulin resistance in the glucose transport process [3, 4]. Insulin activates the glycogen synthase pathway, whereas glycogen synthesis in muscle is markedly reduced in T2DM [5, 6]. Despite many years of research, the molecular mechanisms by which metabolic disease promotes insulin resistance in skeletal muscle are not fully understood.
Recent research focused on how lipid species affect glucose metabolism in skeletal muscles. Lipids were also used as molecules to probe the basic mechanisms of ion fragmentation following electron ionization [7]. However, fundamental studies using mass spectrometry analysis of lipids demonstrate that lipid species are associated with insulin resistance in obesity and diabetes [8-11]. This chapter presents the cellular and molecular mechanisms of obesity- and diabetes-induced insulin resistance in skeletal muscle.
MUSCLE GLUCOSE TRANSPORTER IN OBESITY AND DIABETES
Glucose is a key metabolic substrate for the whole body. Muscle tissues require glucose as an energy source for adenosine triphosphate (ATP) production [12]. Glucose metabolism starts with transport across the plasma membrane [13]. Skeletal muscles take up glucose in response to insulin stimulation and exercise. The insulin receptor (IR), insulin receptor substrates (IRS), and phosphatidylinositol 3-kinase (PI3K) activation are essential components of the insulin-induced response. Eventually, blood glucose is taken into intramyocellular through glucose transporter 4 (GLUT4) translocation [14, 15]. GLUT4 is an insulin-regulated glucose transporter that is responsible for glucose uptake in muscle. It is mainly located in intracellular vesicles in the absence of insulin [16]. Obesity and T2DM are strongly linked to the development of insulin resistance within the skeletal muscles [17]. In 1975, Kemmer et al. demonstrated that the skeletal muscles of obese rats are insulin-resistant with respect to both glucose-transport mechanisms and intracellular pathways of glucose metabolism [18]. Consistent with this, the expression of GLUT4 can explain the insulin-resistant glucose uptake characteristic of dietary-induced obesity [19]. A previous study revealed that transgenic overexpression of GLUT4 enhances glucose tolerance in lean and obese mice [20]. Taken together, increasing muscle GLUT4 content is an important target for improving glucose tolerance in obesity.
The main molecule pathway for glucose uptake through GLUT4 is the PI3K/AKT signaling pathway. The PI3K/AKT pathway is a central regulator in cellular physiology for growth factor signals and critical cellular processes [21]. PI3K and serine/threonine kinase 1 (Akt) signaling is important for insulin-stimulated glucose uptake in skeletal muscle tissues. AKT phosphorylates are involved in the regulation of GLUT4 translocation [22]. PI3K/AKT signaling pathway exists in various organs, but obesity and T2DM impair PI3K/AKT signaling [22]. Sano et al. demonstrated that insulin increases the phosphorylation of AS160 and GLUT4 translocation in 3T3-L1 adipocytes [23]. In human skeletal muscles, exercise increases AS160 phosphorylation without insulin infusion [24]. Similarly, obese rodent muscles decrease glucose uptake with decreased AS160 phosphorylation on Ser588 with or without insulin stimulation [25].
AMP-activated protein kinase (AMPK) increases glucose uptake through PI3K/Akt signaling. For instance, loss of skeletal muscle AMPK exacerbates glucose intolerance and insulin resistance in obese people, resulting in a significant decrease in glucose uptake in skeletal muscles [26]. Indeed, loss of AMPK activity has been observed in the skeletal muscle of patients with obesity and diabetes [27, 28]. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) reportedly activates AMPK and stimulates glucose uptake by skeletal muscle [29], suggesting a drug target to facilitate muscle glucose uptake in obesity and diabetes [30]. Long-term AICAR improves glucose metabolism in insulin-resistant obese mice, which can be explained by effects on muscle glucose uptake [31]. However, a previous report has reported that the stimulatory effects of AICAR on glucose uptake are reduced in older men, irrespective of type 2 diabetes, suggesting that AICAR has only a limited therapeutic effect on older type 2 diabetic skeletal muscles [32].
TBC1D1 and TBC1D4, the two Rab GTPase-activating proteins, are closely related to the GLUT4 translocation to the plasma membrane, resulting in increased glucose uptake [33]. The phosphorylation of TBC1D1 and TBC1D4 has been defined as targets for the AKT and the AMPK [34]. Insulin increases in AS160 phosphorylation in skeletal muscle tissues [35] and cells [36]. Deletion of phosphorylated AS160 exhibits reduced insulin-induced GLUT4 translocation in adipocytes and muscle cells [23, 37]. Therefore, AS160 phosphorylation induces glucose uptake into muscles through the translocation of GLUT4 vesicles. On the other hand, insulin-stimulated AS160 phosphorylation is reduced in T2DM [38]. However, reduced muscle glucose uptake of obesity is not associated with the AKT/AS160 content [39]. Therefore, underlying mechanisms for the impaired glucose uptake in metabolic disease are not completely understood.
In type 1 diabetic rodent models induced streptozocin, NPC43 can effectively increase glucose uptake by activating PI3K, Akt, and AS160 pathways through insulin receptors [40]. Akt and AMPK phosphorylated proteins to vesicle traffic appear to be dependent on linking to small GTPase of the Rab family [41]. When activated, Akt by insulin or muscle contraction phosphorylates AS160 and TBC1D1. Muscle contraction through both energy depletion and increased intracellular calcium leads to activation of AMPK via LKB1 and Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). These proteins lead to AS160 and TBC1D1 phosphorylation. This is thought to regulate the function of these proteins and GLUT4 trafficking by largely uncharacterized mechanisms independent of insulin receptor substrate. On the other hand, overexpression of TBC1D1 does not alter glucose uptake-induced insulin or contraction [42].
MUSCLE GLUCOSE TRANSPORTER IN EXERCISE
Physical exercise is an effective preventive method to prevent obesity and T2DM [43, 44]. It is well established that exercise improves glucose metabolism with T2DM, and adaptations to skeletal muscles are essential for this improvement [17]. Glucose uptake into muscle increases depending on exercise intensity and exercise duration in healthy humans [45]. Exercise increases muscle glucose uptake in diabetic patients like healthy people [46]. The most famous feature of exercise is insulin-independent glucose uptake. Genetic rodent models of muscle-specific insulin receptor knockout do not increase exercise-induced glucose uptake [47], suggesting that exercise promotes insulin-independent signaling pathways for increased glucose uptake. Exercise changes energy status, resulting in increased AMP levels and then induced activation of AMPK. These are the most widely studied proteins implicated in glucose uptake in response to exercise [48]. Meanwhile, AS160, a Rab GTPase-activating protein, is involved in AMPK signaling to glucose uptake. For instance, AICAR increases both AMPK and phosphorylation of AS160 by insulin-independent mechanisms [49]. CaMKII, AS160, and TBC1D1 are also linked to a mechanism for AMPK signaling [50] (Fig. 1).
Fig. (1)) Schematic diagram of the cellular mechanisms for glucose uptake induced by insulin- and muscle contraction (Exercise).Exercise training is also an important recommendation for the management of diabetes due to improving insulin sensitivity in patients [51]. The review from Jensen et al. discusses the following: 1. the insulin sensitivity is increased for up to a single bout of exercise [52]. 2. Exercise training improves insulin sensitivity and glucose uptake [53]. Therefore, exercise can improve dysfunctional insulin pathways and augment glucose uptake in insulin resistance to normalize glycemic control in metabolic disease [54]. On the other hand, some training protocols fail to improve glucose tolerance and prevent a decrease in body weight and mass of adipose tissue [55]. Exercise training decreases glucose uptake during exercise despite a large increase in GLUT4 protein content [45]. For instance, eccentric exercise impairs glucose uptake in skeletal muscle [56]. Indeed, muscle GLUT-4 content is decreased after eccentric contractions [57]. Another study demonstrates that metabolic pathway dysregulations in obesity were improved with vigorous physical exercise [58]. In addition, another study demonstrated that mechanical overload stimulates muscle glucose uptake independent of GLUT4 content [59]. A previous study using the genetic rodent models (muscle-specific GLUT4 knockout) confirmed that GLUT4 is not necessary for overload-induced muscle glucose uptake [61]. GLUT1 also does not mediate basal muscle glucose uptake induced by overload, suggesting that different exercise protocols (eccentric contraction, mechanical overload, endurance running, etc.) have different mechanisms for muscle glucose transporter [62] (Fig. 2).
Fig. (2)) The influence of exercise (acute and or training) on insulin action. These are summarized in Jensen et al. [60].Obese and type 2 diabetic subjects have attenuated AMPK and phosphorylation of AS160 induced by exercise [28]. GLUT4 translocation is impaired in T2DM, whereas exercise results in a normal increase in GLUT4 translocation and glucose uptake. Genetic loss of AMPK function in skeletal muscle has been identified as decreased glucose uptake, but it is unclear in basal systemic glucose metabolism [63]. A recent study demonstrated that a non-selective activator of all AMPK complexes activator caused a decrease in blood glucose in diabetic mice [64]. In contrast, metformin, an activator on AMPK, did not affect glucose uptake at relevant pharmacological concentrations in initial reports [65]. These phenomena indicate that exercise-induced glucose uptake in diabetic patients could not be explained by action of AMPK activation.
MUSCLE LIPID AND INSULIN RESISTANCE IN OBESITY AND DIABETES
The accumulation of intramyocellular lipids may lead to insulin resistance in skeletal muscle. Lipid intermediates directly impair muscle insulin signaling. De novo lipid synthesis might contribute to glucose disposal when glycogen stores are filled. Muscle insulin resistance caused by lipid accumulation alters the subcellular localization of diacylglycerols (DAGs) and ceramides, accelerates peripheral inflammation and damage, and leads to heart failure, nonalcoholic fatty liver disease, obesity, renal anemia, and sarcopenia besides diabetes [66]. Recent research focused on how ceramides and phospholipids alter muscle composition and cause insulin resistance during obesity and diabetes. Ceramides induce insulin resistance in cultured cells by inhibitory effects on insulin signaling [67]. In obesity, the reduction of insulin stimulates glucose uptake and is associated with increased intramyocellular ceramide content [68]. Importantly, sarcopenia involves ceramide content, but insulin resistance was not fully investigated [69]. Previous studies demonstrate that sphingolipid mediators, including ceramide and sphingosine 1-phosphate, influence obesity and glucose metabolism [70-72
