Attenuation of unloading-induced rat soleus atrophy with the heat-shock protein inducer 17-(allylamino)-17-demethoxygeldanamycin

FASEB J. 2012 Oct;26(10):4295-301. doi: 10.1096/fj.12-204412. Epub 2012 Jul 2.

Abstract

We hypothesized that pharmacological induction of HSP70 would attenuate soleus atrophy development under 3 d of rat hindlimb unloading. Male Wistar rats were divided into control (C; n=7), 3-d hindlimb unloading (HUL; n=7), HUL with HSP90 inducer administration, 17-allylamino-17-emethoxygeldanamycin (17-AAG; 60 mg/kg, HUL+17-AAG, n=8). The relative weight of soleus muscle to body weight [soleus wt (mg)/body wt (g)] in the HUL group was less than that of the C and HUL+17-AAG groups (P<0.05). We revealed HSP90, HSP70 mRNA decrease in the HUL group (but not the HUL+17-AAG group) vs. C (P<0.05). The unloading resulted in significant increases of μ-calpain and conjugated ubiquitin (Ub) levels (proteins as well as mRNAs) vs. the C group, whereas 17-AAG administration prevented these alterations (studied by SDS-PAGE and RT-PCR). pFOXO3 protein was decreased in the HUL group vs. C, but not in HUL+17-AAG. Content of E3-lygase (MuRF-1, MAFbx) mRNA was increased in both suspended groups. In summary, 17-AAG administration attenuates soleus muscle atrophy, μ-calpain, and Ub increases under hindlimb unloading as well as decrease of pFOXO3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones / therapeutic use*
  • Blotting, Western
  • Calpain / metabolism
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Hindlimb / drug effects
  • Hindlimb / metabolism
  • Hindlimb / pathology
  • Lactams, Macrocyclic / therapeutic use*
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / drug therapy*
  • Muscular Atrophy / metabolism
  • Rats
  • Rats, Wistar
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Benzoquinones
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Ubiquitin
  • tanespimycin
  • Ubiquitin-Protein Ligases
  • Calpain
  • mu-calpain