C1q Tumor Necrosis Factor α-related Protein Isoform 5 Is Increased in Mitochondrial DNA-depleted Myocytes and Activates AMP-activated Protein Kinase

Abstract

Depletion of mtDNA in myocytes causes insulin resistance and alters nuclear gene expression that may be involved in rescuing processes against cellular stress. Here we show that the expression of C1q tumor necrosis factor ␣-related protein isoform 5 (C1QTNF5) is drastically increased following depletion of mtDNA in myocytes. C1QTNF5 is homologous to adiponectin in respect to domain structure, and its expression and secretion from myocytes correlated negatively with the cellular mtDNA content. Similar to adiponectin, C1QTNF5 induced the phosphorylation of AMP-activated protein kinase (AMPK), leading to increased cell surface recruitment of GLUT4 and increased glucose uptake. Treatment of cells with purified recombinant C1QTNF5 increased the phosphorylation of acetyl-CoA carboxylase and stimulated fatty acid oxidation. C1QTNF5-mediated phosphorylation of AMPK or acetyl-CoA carboxylase was unaffected by depletion of adiponectin receptors such as AdipoR1 or AdipoR2, which indicated that adiponectin receptors do not participate in C1QTNF5-induced activation of AMPK. Serum C1QTNF5 levels were significantly higher in obese/diabetic animals (OLETF rats, ob/ob mice, and db/db mice). These results highlight C1QTNF5 as a putative biomarker for mitochondrial dysfunction and a potent activator of AMPK.

Myonectin (CTRP15), a Novel Myokine That Links Skeletal Muscle to Systemic Lipid Homeostasis

“…We designated this novel cDNA and its encoded protein CTRP15/myonectin. While current work was ongoing, Lim et al (31) reported on a distantly related but distinct C1q family member, CTRP5 (C1qTNF5), in human and had inadvertently coined the term myonectin for CTRP5, although that term was not used in a previous CTRP5 study by the same authors (32). Given that mouse myonectin cDNA and protein sequences (HQ285249 and ADP00570, respectively) were deposited in the GenBank database and released to the public prior to the study by Lim et al (31), we propose that CTRP5 retains its original designation (20,33) and CTRP15 retains its current designation as myonectin to prevent confusion in nomenclature.…”

Metabolic Regulation by C1q/TNF-related Protein-13 (CTRP13)

“…Besides CTRP13, recent studies show that CTRP5 and CTRP6 can also activate the AMPK signaling pathway to promote glucose uptake and fatty acid oxidation (18,19). Although bacterially produced recombinant GST-CTRP5 fusion protein can activate the AMPK signaling pathway in mouse myotubes (18), its prominent expression in the eye suggests a primary role in the visual system (14,45).…”

“…Although bacterially produced recombinant GST-CTRP5 fusion protein can activate the AMPK signaling pathway in mouse myotubes (18), its prominent expression in the eye suggests a primary role in the visual system (14,45). Indeed, mutation in the CTRP5 gene has been found to cause late onset macular degeneration in humans (45,71).…”

Cardiovascular and Metabolic Regulation by the Adiponectin/C1q/Tumor Necrosis Factor–Related Protein Family of Proteins

“…14 CTRP5 has been shown to promote AMPK signaling in cultured myotubes, thereby leading to increased glucose uptake. 15 CTRP13 has also been shown to stimulate glucose uptake in adipocytes, myotubes, and hepatocytes in vitro through its ability to promote AMPK signaling, suggesting a role in glucose metabolism. 16 Furthermore, transgenic overexpression of CTRP1 will activate AMPK signaling in skeletal muscle and ameliorate metabolic dysfunction under conditions of overnutrition.…”