Abstract
BackgroundInhibition of Hsp90 has been shown to improve glucose tolerance and insulin sensitivity in mouse models of diabetes. In the present report, the specific isoform Hsp90ab1, was identified as playing a major role in regulating insulin signaling and glucose metabolism.MethodsIn a diet-induced obese (DIO) mouse model of diabetes, expression of various Hsp90 isoforms in skeletal tissue was examined. Subsequent experiments characterized the role of Hsp90ab1 isoform in glucose metabolism and insulin signaling in primary human skeletal muscle myoblasts (HSMM) and a DIO mouse model.ResultsIn DIO mice Hsp90ab1 mRNA was upregulated in skeletal muscle compared to lean mice and knockdown using anti-sense oligonucleotide (ASO) resulted in reduced expression in skeletal muscle that was associated with improved glucose tolerance, reduced fed glucose and fed insulin levels compared to DIO mice that were treated with a negative control oligonucleotide. In addition, knockdown of HSP90ab1 in DIO mice was associated with reduced pyruvate dehydrogenase kinase-4 mRNA and phosphorylation of the muscle pyruvate dehydrogenase complex (at serine 232, 293 and 300), but increased phosphofructokinase 1, glycogen synthase 1 and long-chain specific acyl-CoA dehydrogenase mRNA. In HSMM, siRNA knockdown of Hsp90ab1 induced an increase in substrate metabolism, mitochondrial respiration capacity, and insulin sensitivity, providing further evidence for the role of Hsp90ab1 in metabolism.ConclusionsThe data support a novel role for Hsp90ab1 in arbitrating skeletal muscle plasticity via modulation of substrate utilization including glucose and fatty acids in normal and disease conditions. Hsp90ab1 represents a novel target for potential treatment of metabolic disease including diabetes.
Highlights
Inhibition of Hsp90 has been shown to improve glucose tolerance and insulin sensitivity in mouse models of diabetes
Diet-induced obesity induces Hsp isoform specific alterations in skeletal muscle The expression of various isoforms of Hsp90 was examined to determine if Hsp regulation of metabolism is isoform specific
It is of interest to further examine whether the nutrition-mediated alteration in HSP90β could be uniquely involved in skeletal muscle metabolism
Summary
Inhibition of Hsp has been shown to improve glucose tolerance and insulin sensitivity in mouse models of diabetes. The specific isoform Hsp90ab, was identified as playing a major role in regulating insulin signaling and glucose metabolism. Isoform specific knockdown of HSP90ab by treatment with antisense oligonucleotide (ASO) improved glucose tolerance and was associated with alterations in expression and activity of key metabolic pathway molecules in skeletal muscle of DIO mice. In in vitro studies using primary human skeletal muscle myotubes (HSMM) siRNA knockdown of HSP90ab was associated with significant improvement in substrate metabolism, insulin sensitivity and glucose homeostasis. Knockdown of Hsp90ab does not affect the expression of proteins within the canonical Hsp pathway that includes HSF1, Hsp, TRAF1 and Hsp70 Together, these data demonstrate that Hsp90ab is a key regulator of skeletal muscle metabolism and represents a viable therapeutic target for management of insulin resistance and metabolic disease
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