Muscle-Specific Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Increases Peripheral Glucose Disposal and Insulin Sensitivity

Abstract

Physical exercise ameliorates metabolic disorders such as type 2 diabetes mellitus and obesity, but the molecular basis of these effects remains elusive. In the present study, we found that exercise up-regulates heparin-binding epidermal growth factor-like growth factor (HB-EGF) in skeletal muscle. To address the metabolic consequences of such gain of HB-EGF function, we generated mice that overexpress this protein specifically in muscle. The transgenic animals exhibited a higher respiratory quotient than did wild-type mice during indirect calorimetry, indicative of their selective use of carbohydrate rather than fat as an energy substrate. They also showed substantial increases in glucose tolerance, insulin sensitivity, and glucose uptake by skeletal muscle. These changes were accompanied by increased kinase activity of Akt in skeletal muscle and consequent inhibition of Forkhead box O1-dependent expression of the pyruvate dehydrogenase kinase 4 gene. Furthermore, mice with a high level of transgene expression were largely protected from obesity, hepatic steatosis, and insulin resistance, even when maintained on a high-fat diet. Our results suggest that HB-EGF produced by contracting muscle acts as an insulin sensitizer that facilitates peripheral glucose disposal.

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

“…However, other ERBB ligands could be involved in regulating ERBB activation in db/db mice. Indeed, other ligands, which have been involved in metabolic disorders, can modulate ERBB phosphorylation state 25 , such as NRG4 26, 27 , betacellulin 28, 29 , epiregulin 30 or proheparin-binding EGF-like growth factor (HB-EGF) 31, 32 . As many biological processes can be regulated through ERBB, the functional consequences of the modified ERBB abundance and phosphorylation state in diabetes are difficult to predict.…”

Intramuscular VEGF repairs the failing heart: role of host-derived growth factors and mobilization of progenitor cells

“…In addition to VEGF, the ability of skeletal muscle to function as a trophic factor-producing organ has increasingly been recognized (40,62). Several cytokines and growth factors, including EGF, FGF, HGF, IGF, and NGF have all been shown to be produced by skeletal myocytes (3,15,22,56,60). However, the capacity for trophic factor production can be aberrantly downregulated, as seen in human dilated cardiomyopathy for VEGF (1) and human heart failure for NGF (24).…”

Modulation of SIRT1-Foxo1 Signaling axis by Resveratrol: Implications in Skeletal Muscle Aging and Insulin Resistance

“…3). It has been reported that insulin stimulation increased the phosphorylations of Akt at Ser473/Thr308 and Foxo1 at Thr24 and reduced the mRNA content of PDK4 in the gastrocnemius muscle [38]. It is noteworthy that the elevation of Foxo1 phosphorylation was accompanied by increased whole-body glucose uptake and attenuated hepatic glucose production [38].…”

“…It has been reported that insulin stimulation increased the phosphorylations of Akt at Ser473/Thr308 and Foxo1 at Thr24 and reduced the mRNA content of PDK4 in the gastrocnemius muscle [38]. It is noteworthy that the elevation of Foxo1 phosphorylation was accompanied by increased whole-body glucose uptake and attenuated hepatic glucose production [38]. In contrast, experimental simulation of insulin-resistant states by infusion of intralipid/lactate and insulin in rats reduced the protein contents of phosphorylated Akt Ser307 and Foxo1 Ser319 and induced transcriptional activation of PDK4 in the gastrocnemius muscle [39].…”

“…In contrast, resveratrol was observed to increase the SIRT1 deacetylase activity and alleviate the elevations of protein contents of acetylated Foxo1, atrogin1 and MuRF-1 in dexamethasone-treated L6 myotubes [57]. Although it is well-established that the activity of PDH, a glycolytic enzyme in skeletal muscle would be blunted in response to phosphorylation and inactivation of Foxo1 [38,39,40], how acetylation/deacetylation mechanisms would modulate the activity of Foxo1, expression of PDK4 and the subsequent glucose utilization in the aging skeletal muscle are poorly understood. It has been reported that the protein content of SIRT1 was increased with concomitant reduction of acetylation status of Foxo1 in the skeletal muscle of diabetic patients following a 3-month intake of epicatechin-containing drink [58].…”