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To better understand Cardarine and its benefits, we need to more closely examine its two main modes of action, PPARd agonism and AMPk activation.
PPAR receptors are a group of nuclear receptors that can be divided into three subtypes: alpha, beta, and delta. All three are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism, and as such are typically activated by fatty acids and their metabolites. Although distributed throughout the body, each type tends to be dominant in certain biological tissues. PPARa is the main subtype in liver, PPARb the main subtype in adipose tissue, and PPARd in the colon, intestine, liver, heart, lung, brain, and skeletal muscle, the latter in which it is the most abundant PPAR.
PPARd activation leads to upregulation of energy expenditure by fatty acid oxidation, lowered serum triglyceride (approx. 50%) and free fatty acid levels, and decreased lipid accumulation. Activation of PPARd in adipose tissue protects against diet-induced obesity and type ll diabetes. Furthermore, it also activates the heat-producing uncoupling enzymes in brown adipose tissue and muscle. When PPARd is activated by the agonist Cardarine, there is a tendency for an increase in HDL (up to 80%) and a lowering of LDL (up to 30%). This phenomenon has been observed in both animal and human studies.
Fatty acid oxidation is the primary source of energy in the postnatal heart. Impaired fatty acid oxidation and a shift to reliance on glucose metabolism are hallmarks of myocardial diseases such as cardiac hypertrophy and congestive heart failure. As in skeletal muscle, PPARd is a critical regulator of fatty acid oxidation in cardiac tissue.
Skeletal muscle is a key metabolic tissue, accounting for approximately 80% of insulin-stimulated glucose uptake. It is also one of the most metabolically demanding tissues, relying heavily on fatty acids as an energy source. Muscle is a major site of glucose metabolism and fatty acid oxidation, and is a key target tissue in orchestrating this scenario, because it is a key organ for lipid oxidation and glucose uptake. Indeed, improvements in skeletal muscle insulin sensitivity are beneficial to control glucose homeostasis. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile, and lipid metabolism.
Muscle is composed of heterogeneous myofibers that differ in their metabolic and contractile properties, including oxidative slow-twitch (type I), mixed oxidative/glycolytic fast-twitch (type IIA), and glycolytic fast-twitch (type IIB) forms. Oxidative myofibers preferentially express enzymes that oxidize fatty acids and contain slow isoforms of contractile proteins, whereas glycolytic myofibers predominantly metabolize glucose and are composed of fast contractile protein isoforms.
PPARd is expressed in skeletal muscle at 10- and 50-fold higher levels compared with PPARa and PPARb, respectively, and it is preferentially found in oxidative rather than glycolytic myofibers.
PPARd’s regulation of metabolic and fiber type status has several physiological implications. First, the presence of an increased proportion of oxidative slow-twitch fibers is predicted to decrease skeletal muscle fatigability. For example, increased endurance in marathon runners is linked to a higher proportion of oxidative slow-twitch fibers in their skeletal muscles. Second, oxidative fibers have a tremendous impact on fatty acid homeostasis. Both obesity and insulin resistance are linked to a decrease in the proportion of oxidative slow-twitch fibers in skeletal muscle. With subjects who have a higher proportion of oxidative slow-twitch fibers are resistant to high-fat diet-induced obesity.
Activation of PPARd during high-fat feeding increases disposal of lipid in skeletal muscles, preventing the storage of excess fat in adipocytes and weight gain. This metabolic remodeling of skeletal muscle may also be responsible for the insulin-sensitizing effects of PPARd agonists in high-fat diet–induced and genetic models of obesity. Interestingly, in vitro studies also show that PPARd agonist treatment of cultured human skeletal muscle increases insulin-independent glucose uptake.
Skeletal muscle is highly plastic, adapting to environmental challenges by regulating the composition of slow- and fast-twitch myofibers. Interventions including endurance exercise, physical inactivity, and metabolic diseases such as type 2 diabetes mellitus can induce the trans-differentiation of myofibers. It has been demonstrated that PPARd activation by Cardarine can lead to muscle fiber switching; specifically, type ll fibers become more oxidative and display the functional hallmarks of type l fibers.
The AMPk Connection:
Increases in fatty acid oxidation induced by Cardarine are dependent on both PPARd and AMPK. PPARd activation can increase the activity of AMPK, and the increase in fatty acid oxidation in human skeletal muscle cells after Cardarine treatment is dependent on both PPARd and AMPK. Cardarine-mediated increase in glucose uptake requires AMPK but not PPARd; the effect of Cardarine on glucose uptake appears to be PPARd-independent and requires AMPK activation. Thus, Cardarine, in a manner analogous to a number of other chemical compounds (eg metformin) exerts direct and indirect effect(s) on mitochondrial machinery. In short, the PPARd agonist Cardarine promotes changes in lipid/glucose metabolism and gene expression in human skeletal muscle cells by PPARd- and AMPK-dependent and -independent mechanisms.
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