Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

Abstract

Aims/hypothesis Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF. Methods We first examined whether exercise induced BDNF expression in humans. Next, C2C12 skeletal muscle cells were electrically stimulated to mimic contraction. L6 myotubes and isolated rat extensor digitorum longus muscles were treated with BDNF and phosphorylation of the proteins AMP-activated protein kinase (AMPK) (Thr 172 ) and acetyl coenzyme A carboxylase β (ACCβ) (Ser 79 ) were analysed, as was fatty acid oxidation (FAO).Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice. Results BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation. Bdnf mRNA and protein expression was increased in muscle cells that were electrically stimulated. BDNF increased phosphorylation of AMPK and ACCβ and enhanced FAO both in vitro and ex vivo. The effect of BDNF on FAO was AMPK-dependent, since the increase in FAO was abrogated in cells infected with an AMPK dominant negative adenovirus or treated with Compound C, an inhibitor of AMPK. Electroporation of a Bdnf expression

Myokines in insulin resistance and type 2 diabetes

“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”

“…BDNF mRNA expression and protein has been detected in human skeletal muscle and C2C12 cells [46], and our group recently reported BDNF in the supernatant fraction of human myotubes [2]. While in patients with type 2 diabetes circulating levels of BDNF are decreased independently of obesity [47], exercise has been demonstrated to increase serum BDNF levels and BDNF mRNA and protein expression in human skeletal muscle [46]. However, it has been shown in humans that 70-80% of circulating BDNF originates from the brain during both rest and after exercise, suggesting the brain as the major source of this factor [48].…”

“…However, it has been shown in humans that 70-80% of circulating BDNF originates from the brain during both rest and after exercise, suggesting the brain as the major source of this factor [48]. In vitro studies using C2C12 cells have shown that BDNF increases fatty acid oxidation (Table 1) via activation of AMPK and phosphorylation of acetyl-CoA carboxylase [46]. While BDNF has no direct effect on glucose uptake or gluconeogenesis in primary cultured hepatocytes, L6 myotubes or 3T3-L1 adipocytes [49], a potential effect on lipolysis has not been studied so far.…”

Early postoperative pelvic-floor biofeedback improves erectile function in men undergoing radical prostatectomy: a prospective, randomized, controlled trial

“…44--46 Moreover, experimental studies have demonstrated that contraction of skeletal muscle can induce the release of neurotrophic factors. Matthews et al 47 have shown in an animal model that muscle contraction induces an increase in brain-derived neurotrophic factor in muscle cells, which has an important role in regulating neuronal growth.…”

短跑运动员血浆中脑源性神经营养因子水平较普通人群显著升高

“…BDNF is produced and secreted within the central nervous system and peripherally [2] by vascular endothelial cells [3] , skeletal muscle cells [4] , smooth muscle cells [4] and immune cells [5] . Since BDNF crosses the blood-brain barrier in both directions, it is thought that circulating BDNF is transported into the brain and contributes to homeostasis [6] .…”