Endocrine Abstracts

Insulin resistance, type 2 diabetes, and obesity accelerate muscle protein degradation (MPD) via the ubiquitin-proteasome (UPS) and autophagy-lysosome pathways (ALP). Although associations exist between ubiquitin E3 ligases and class IIa histone deacetylases (HDACs), and between elevated HDAC4/5 levels and impaired oxidative metabolism, the precise link between HDAC5 and muscle atrophy remains unknown. In a previous unpublished in vivo study, our group showed HDAC5 overexpression for 3 months reduced skeletal muscle mass by ~20%; however, contrary to the hypothesis that atrophy is caused by reduced protein synthesis, these atrophied muscles displayed increased protein synthesis. To better understand these unexpected results and the underlying mechanism of wasting, we investigated the time-dependent effects of AAV-mediated HDAC5 overexpression in mouse skeletal muscle. In this time-course study, HDAC5 overexpression induced muscle atrophy, with significant mass reduction at 4 and 8 weeks and a trend at 2 weeks. Mechanistically, we confirmed a counterintuitive increase in absolute newly synthesized protein at 8 weeks, ruling out protein synthesis inhibition as the primary cause. We found a distinct temporal pattern in the proteolytic pathways: UPS activation was delayed (E3 ligases and protein ubiquitinylation increased only at 8 weeks), failing to account for the early 2-week muscle loss. Crucially, ALP activation was early and dominant: key autophagy markers LC3B-II and p62 were significantly elevated at 2, 4, and 8 weeks post-AAV, strongly correlating with initial muscle mass reduction. Furthermore, increased levels of phospho-AMPKα (Thr172) at 4 and 8 weeks suggest a potential role for AMPK signalling in the HDAC5-induced ALP activation. In conclusion, HDAC5 overexpression induces rapid skeletal muscle atrophy through the early and sustained activation of the ALP. This suggests ALP activation is the initial and dominant mechanism responsible for HDAC5-induced muscle atrophy. Further investigation is needed to define the precise regulation between HDAC5 and the AMPKα/ALP axis.