Abstract
Mouse olfactory receptor 544 (Olfr544) is ectopically expressed in varied extra-nasal organs with tissue specific functions. Here, we investigated the functionality of Olfr544 in skeletal muscle cells and tissue. The expression of Olfr544 is confirmed by RT-PCR and qPCR in skeletal muscle cells and mouse skeletal muscle assessed by RT-PCR and qPCR. Olfr544 activation by its ligand, azelaic acid (AzA, 50 μM), induced mitochondrial biogenesis and autophagy in cultured skeletal myotubes by induction of cyclic adenosine monophosphate-response element binding protein (CREB)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-extracellular signal-regulated kinase-1/2 (ERK1/2) signaling axis. The silencing Olfr544 gene expression abrogated these effects of AzA in cultured myotubes. Similarly, in mice, the acute subcutaneous injection of AzA induced the CREB-PGC-1α-ERK1/2 pathways in mouse skeletal muscle, but these activations were negated in those of Olfr544 knockout mice. These demonstrate that the induction of mitochondrial biogenesis in skeletal muscle by AzA is Olfr544-dependent. Oral administration of AzA to high-fat-diet fed obese mice for 6 weeks increased mitochondrial DNA content in the skeletal muscle as well. Collectively, these findings demonstrate that Olfr544 activation by AzA regulates mitochondrial biogenesis in skeletal muscle. Intake of AzA or food containing AzA may help to improve skeletal muscle function.
Highlights
Olfactory receptors (ORs) are G-protein coupled receptors (GPCR), which are mainly expressed in the cilia of the olfactory epithelium (Buck and Axel, 1991)
This raised the possibility that mitochondria in skeletal muscle cells could be targets to prevent type 2 diabetes mellitus (Goodpaster, 2013; Hesselink et al, 2016), and these biological processes can be regulated by natural substances and food molecules
We believe that olfactory receptor 544 (Olfr544) in extra-nasal tissues such as skeletal muscle can be endogenously stimulated by AzA derived from diet or endogenous synthesis
Summary
Olfactory receptors (ORs) are G-protein coupled receptors (GPCR), which are mainly expressed in the cilia of the olfactory epithelium (Buck and Axel, 1991). The functionalities of Abbreviations: Azelaic acid, AzA; cyclic adenosine monophosphate, cAMP; cAMP-response element binding protein, CREB; extracellular signal-regulated kinase-1/2, ERK1/2; G-protein coupled receptors, GPCR; high fat diet, HFD; mitochondrial transcription factor A, TFAM; olfactory receptors, ORs; olfactory receptor 544, Olfr544; protein kinase A, PKA; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1α; small interfering RNA, siRNA. MOR23 activation stimulates the cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in skeletal muscle tissue This pathway regulates the migration and adhesion of skeletal muscle cells, thereby contributing to wound healing and tissue repair (Griffin et al, 2009). Olfr544 is expressed in pancreatic α-cells to stimulate glucagon secretion (Kang et al, 2015) These results suggest that ectopic ORs expressed in non-nasal tissues can play a role in functional GPCR proteins and stimulate unique signal transduction pathways, resulting in tissue-specific roles by recognizing odorants as ligand molecules
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