AXIN-AMPK signaling: Implications for healthy aging.

Avijit Mallick,Bhagwati P Gupta

doi:10.12688/f1000research.74220.1

Abstract

The energy sensor AMP kinase (AMPK) and the master scaffolding protein, AXIN, are two major regulators of biological processes in metazoans. AXIN-dependent regulation of AMPK activation plays a crucial role in maintaining metabolic homeostasis during glucose-deprived and energy-stressed conditions. The two proteins are also required for muscle function. While studies have refined our knowledge of various cellular events that promote the formation of AXIN-AMPK complexes and the involvement of effector proteins, more work is needed to understand precisely how the pathway is regulated in response to various forms of stress. In this review, we discuss recent data on AXIN and AMPK interaction and its role in physiological changes leading to improved muscle health and an extension of lifespan. We argue that AXIN-AMPK signaling plays an essential role in maintaining muscle function and manipulating the pathway in a tissue-specific manner could delay muscle aging. Therefore, research on understanding the factors that regulate AXIN-AMPK signaling holds the potential for developing novel therapeutics to slow down or revert the age-associated decline in muscle function, thereby extending the healthspan of animals.

Highlights

With aging, there is a decline in skeletal muscle mass and function
Work in the nematode C. elegans has revealed that the AXIN family member PRY-1 is necessary for animals’ normal motility and health, and its activated form promotes longevity by maintaining muscle mitochondrial homeostasis.[4]
A similar function was previously ascribed to the AMP kinase (AMPK) catalytic subunit homolog AAK-2.5,6 The genetic and biochemical experiments revealed that PRY-1 and AAK-2 work together, likely through protein-protein interaction, and PRY-1 is required for AAK-2-mediated beneficial effect on muscle health and lifespan (Figure 1)

Summary

Introduction

There is a decline in skeletal muscle mass and function. Aging muscle undergoes a shift in the balance between myogenic potential and fibrogenic activity that leads to reduced capacity of the muscle to repair and regenerate.[1]. These same treatments, i.e., metformin and glucose deprivation, are known to extend the lifespan in an AAK-2-dependent manner.[37,38] Overall, these studies demonstrate that AXIN homologs in every system have shared as well as unique functions Whether these proteins can redundantly activate AMPK remains to be investigated. While the AXIN-AMPK complex is localized to lysosomes and cytoplasm, the changes in their activities in response to external stimuli are poorly understood.[10,12] Both factors are broadly expressed and in overlapping domains; whether their interactions are global or restricted to specific tissues remains to be determined In this regard, it is worth mentioning that AMPK functions cell non-autonomously in C. elegans,[24] and we have reported that the protein is needed in both muscles and intestine to mediate beneficial effects of constitutive expression of AXIN in muscles.[4]. More work is needed to understand the role of AXIN-AMPK signaling in exercise-mediated benefits

Conclusion

18. Thomson DM