Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

Abstract

Aging is a significant risk factor for several diseases. Studies have uncovered multiple signaling pathways that modulate the process of aging including the Insulin/IGF-1 signaling (IIS). In C. elegans the key regulator of IIS is DAF-16/FOXO whose activity is regulated by phosphorylation. A major kinase involved in DAF-16-mediated lifespan extension is the AMPK catalytic subunit homolog, AAK-2. In this study, we demonstrate a novel role of PRY-1/Axin in AAK-2 activation to regulate DAF-16 function. The pry-1 transcriptome contains many genes associated with aging and muscle function. Consistent with this, pry-1 is strongly expressed in muscles and musclespecific overexpression of pry-1 extends the lifespan, delays muscle aging, and improves mitochondrial morphology in DAF-16-dependent manner. Furthermore, PRY-1 is necessary for AAK-2 phosphorylation. Together, our data demonstrate a crucial role of PRY-1 in maintaining the lifespan and muscle health. Since muscle health declines with age, our study offers new possibilities to manipulate Axin function to delay muscle aging and improve lifespan.

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle

“…While the current investigation was in progress, AXIN isoforms 1 and 2 were reported to be functionally redundant in their regulation of AMPK (Zong et al 2019). Furthermore, pry-1, the orthologue of AXIN1/2 in C. elegans is strongly expressed in muscles, and was required for aak-2 (AMPK) activation and lifespan extension (Mallick & Gupta, 2020). In skeletal muscle, both AXIN1 and 2 are expressed, with AXIN2 being upregulated during differentiation and being essential for myogenesis (Huraskin et al 2016), making it possible that AXIN2 is functionally compensating for AXIN1.…”

“…2019). Furthermore, pry‐1, the orthologue of AXIN1/2 in C. elegans is strongly expressed in muscles, and was required for aak‐2 (AMPK) activation and lifespan extension (Mallick & Gupta, 2020). In skeletal muscle, both AXIN1 and 2 are expressed, with AXIN2 being upregulated during differentiation and being essential for myogenesis (Huraskin et al .…”