Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Imbalanced PKA-calcineurin signaling impairs mitochondrial health and insulin action in skeletal muscle deficient in estrogen-receptor alpha (ERα) (#164)

Brian G Drew 1 2 , Vicente Ribas 2 , Zhenqi Zhou 2 , Jonathan Wanagat 2 , Peter Tontonoz 3 , Aldons J Lusis 2 , Bente Pedersen 4 , Matthias Tschop 5 , Kenneth Korach 6 , Andrea Hevener 2
  1. BakerIDI Heart & Diabetes Institute, Prahran, VIC, Australia
  2. David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
  3. Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA
  4. Centre for Inflammation and Metabolism, University of Copenhagen, Copenhagen, Denmark
  5. Helmholtz Diabetes Center, Technische Universität München, Munich, Germany
  6. Receptor Biology Section, NIEHS, NIH , Research Triangle, North Carolina, USA

Impaired action of the nuclear hormone receptor, estrogen receptor (ER)α, promotes obesity and metabolic dysfunction in humans and mice; however, the tissues and mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERα expression in muscle is associated with glucose intolerance and adiposity in women and in female mice. To test whether metabolic dysfunction previously observed in whole body ERα-/- mice is attributable to loss of ERα in skeletal muscle, we generated muscle specific ERα knockout (MERKO) mice. Glucose intolerance, insulin resistance, and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice, phenocopying animals with global ERα deficiency. In MERKO muscle, we observed a marked alteration in mitochondrial morphology, overproduction of reactive oxygen species, and an impairment in basal and stress-induced mitochondrial (mt) fission dynamics, which was in part driven by imbalanced PKA-calcineurin signaling and altered DRP1 phosphorylation - a key mediator of mitochondrial fission. Although muscle mtDNA abundance was similar between genotypes, ERα deficiency diminished mtDNA turnover,, which was in turn balanced by a reduction in replication and degradation as a consequence of impaired fission and mitophagy. These findings are consistent with the retention of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease.