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

Abstract

Key points Tamoxifen‐inducible skeletal muscle‐specific AXIN1 knockout (AXIN1 imKO) in mouse does not affect whole‐body energy substrate metabolism. AXIN1 imKO does not affect AICAR or insulin‐stimulated glucose uptake in adult skeletal muscle. AXIN1 imKO does not affect adult skeletal muscle AMPK or mTORC1 signalling during AICAR/insulin/amino acid incubation, contraction and exercise. During exercise, α2/β2/γ3AMPK and AMP/ATP ratio show greater increases in AXIN1 imKO than wild‐type in gastrocnemius muscle. Abstract AXIN1 is a scaffold protein known to interact with >20 proteins in signal transduction pathways regulating cellular development and function. Recently, AXIN1 was proposed to assemble a protein complex essential to catabolic‐anabolic transition by coordinating AMPK activation and inactivation of mTORC1 and to regulate glucose uptake‐stimulation by both AMPK and insulin. To investigate whether AXIN1 is permissive for adult skeletal muscle function, a phenotypic in vivo and ex vivo characterization of tamoxifen‐inducible skeletal muscle‐specific AXIN1 knockout (AXIN1 imKO) mice was conducted. AXIN1 imKO did not influence AMPK/mTORC1 signalling or glucose uptake stimulation at rest or in response to different exercise/contraction protocols, pharmacological AMPK activation, insulin or amino acids stimulation. The only genotypic difference observed was in exercising gastrocnemius muscle, where AXIN1 imKO displayed elevated α2/β2/γ3 AMPK activity and AMP/ATP ratio compared to wild‐type mice. Our work shows that AXIN1 imKO generally does not affect skeletal muscle AMPK/mTORC1 signalling and glucose metabolism, probably due to functional redundancy of its homologue AXIN2.

Gene deletion of γ‐actin impairs insulin‐stimulated skeletal muscle glucose uptake in growing mice but not in mature adult mice

“…However, we found similar γ‐actin expression in the wild‐type and −/− lysate (Figure 1a), likely due to γ‐actin from other cell types dominating γ‐actin pool in whole‐muscle lysate. Thus, we next verified the effective excision of the floxed γ‐actin gene in myofibers by PCR similar to our previous studies (Li et al, 2021; Madsen et al, 2018). This yielded a ~50% reduction in floxed gene content in quadriceps muscle and ~30% in soleus (Figure 1b).…”

LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis

“…The significant obstacles of cardiomyocyte proliferation include: (1) stalled cell cycle, (2) specialized cytoskeleton, and (3) switched metabolic pathway [ 5 , 31 , 32 ]. Interestingly, AMPK is involved in all these three processes: AMPK senses energy stress and enhances catabolic metabolism [ 33 ]; AMPK mediates re-organization of the cytoskeleton [ 34 ], and AMPK inhibits cell proliferation [ 35 ]. Therefore, AMPK is one of the most critical elements in cardiomyocyte proliferation.…”

AXIN-AMPK signaling: Implications for healthy aging

“…While it remains to be seen whether AXIN2 plays a redundant role in this process and regulates AMPK, Li et al . 13 reported no change in AMPK activation following AXIN1 imKO in the skeletal muscle. Furthermore, Zong et al .…”

“…Interestingly, exercise-induced glucose uptake requires AXIN1 in skeletal muscles. While it remains to be seen whether AXIN2 plays a redundant role in this process and regulates AMPK, Li et al 13 reported no change in AMPK activation following AXIN1 imKO in the skeletal muscle. Furthermore, Zong et al 12 showed that AXIN2 could substitute AXIN1 in forming a complex between LKB1 and AMPK.…”

“…12 Intriguingly, it was shown recently that skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) mice are phenotypically normal and exhibited no impairment of AMPK regulation or glucose uptake. 13 Such a phenotype may be explained by redundancies between AXIN1 and its homolog AXIN2. Both proteins are expressed in skeletal muscles, and AXIN2 can functionally replace AXIN1 in regulating AMPK.…”