Abstract
It has been reported that neuregulin1 (NRG1) improves glucose tolerance in healthy and diabetic rodents. In vitro studies also suggest that NRG1 regulates myocyte oxidative capacity. To confirm this observation in vivo, we evaluated the effect on mitochondrial function of an 8-week treatment with NRG1 in db/db diabetic mice and C57BL/6JRJ healthy controls. NRG1 treatment improved complex 2-mediated mitochondrial respiration in the gastrocnemius of both control and diabetic mice and increased mitochondrial complex 2 subunit content by 2-fold. This effect was not associated with an increase in mitochondrial biogenesis markers. Enhanced ERBB4 phosphorylation could mediate NRG1 effects on mitochondrial function through signalling pathways, independently of ERK1/2, AKT or AMPK.
Highlights
Neuregulin 1 (NRG1) is a cytokine that belongs to a family of proteins structurally related to epidermal growth factors (EGF)[1]
In agreement, when primary neonatal rat ventricular myocytes are cultured in the presence of an anti-ERBB2 antibody, they display mitochondrial dysfunction, loss of mitochondrial membrane potential, reduced adenosine triphosphate (ATP) levels and loss of redox capacity caused by activation of the mitochondrial apoptosis pathway[13]
As impaired mitochondrial function could contribute to the pathogenesis of insulin resistance in skeletal muscle[22], we investigated whether chronic treatment with NRG1 improves mitochondrial function in mouse skeletal muscle
Summary
Neuregulin 1 (NRG1) is a cytokine that belongs to a family of proteins structurally related to epidermal growth factors (EGF)[1]. It was shown that 48 h-incubation with NRG1 increases the oxidative capacity and the expression of mitochondrial-specific genes in L6E9 and C2C12 muscle cells These effects are mediated by the peroxisome proliferator-activated receptor beta (PPARβ) and PPAR-gamma coactivator 1-alpha (PGC-1α) signalling pathway[10]. Similar effects are often observed in the heart in response to anticancer therapies that target ERBB214 These findings clearly implicate NRG1/ERBB signalling in the regulation of heart mitochondrial function in vivo. Cells[10], but many data concerning other tissues or cellular models suggest that the NRG1/ERBB pathway could be crucial for the regulation of mitochondrial oxidative capacity in skeletal muscle as well. We tested the hypothesis that NRG1/ERBB abundance and signalling are disturbed in skeletal muscle of db/db mice and that chronic treatment with NRG1 improves mitochondrial function in this animal model of type 2 diabetes
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