Deacetylation inhibition reverses PABPN1-dependent muscle wasting

Reduced PABPN1 levels cause aging-associated muscle wasting. PABPN1 is a multi-functional regulator of mRNA processing. To elucidate the molecular mechanisms causing PABPN1-mediated muscle wasting, we compared the transcriptome to the proteome in mouse muscles expressing shRNA to PABPN1 (shPab). We found greater variations in the proteome as compared to mRNA expression profiles. Protein accumulation in the shPab proteome was concomitant with reduced proteasomal activity. Notably, protein acetylation appeared to be enriched in shPab versus control proteomes (63%). An acetylome study in shPab muscles revealed prominent peptide deacetylation associated with elevated sirtuin-1 (SIRT1) deacetylase. We show that SIRT1 mRNA levels are controlled by PABPN1 via an alternative polyadenylation site utilization. SIRT1 inhibition reversed PABPN1 activity and muscle cell function. Moreover, deacetylation inhibition increased PABPN1 levels and reversed muscle wasting. We suggest that perturbation of a multifactorial regulatory loop involving PABPN1 and SIRT1 plays an imperative role in aging-associated muscle wasting.