β-hydroxy-β-methylbutyrate (HMB) prevents sepsis-induced diaphragm dysfunction in mice

Respir Physiol Neurobiol. 2014 Jun 1;196:63-8. doi: 10.1016/j.resp.2014.02.015. Epub 2014 Mar 12.

Abstract

Infections induce severe respiratory muscle weakness. Currently there are no treatments for this important clinical problem. We tested the hypothesis that β-hydroxy-β-methylbutyrate (HMB) would prevent sepsis-induced diaphragm weakness. Four groups of adult male mice were studied: controls (saline-injected), sepsis (intraperitoneal lipopolysaccharide), sepsis+HMB (injected intravenously), and HMB. Diaphragm force generation and indices of caspase 3, calpain, 20S proteasomal subunit, and double-stranded RNA-dependent protein kinase (PKR) activation were assessed after 24h. Sepsis elicited large reductions in diaphragm specific force generation at all stimulation frequencies. Endotoxin also activated caspase 3, calpain, the 20S proteasomal subunit and PKR in the diaphragm. HMB blocked sepsis-induced caspase 3, 20S proteasomal and PKR activation, but did not prevent calpain activation. Most importantly, HMB administration significantly attenuated sepsis-induced diaphragm weakness, preserving muscle force generation at all stimulation frequencies (p<0.01). We speculate that HMB may prove to be an important therapy in infected patients, with the potential to increase diaphragm strength, to reduce the duration of mechanical ventilation and to decrease mortality in this patient population.

Keywords: Caspase 3; Diaphragm; PKR; Proteolysis; Sepsis; β-Hydroxy-β-methylbutyrate (HMB).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calpain / metabolism
  • Caspase 3 / metabolism
  • Diaphragm / drug effects*
  • Diaphragm / pathology
  • Diaphragm / physiopathology
  • Disease Models, Animal
  • Lipopolysaccharides
  • Male
  • Mice
  • Muscle Strength / drug effects
  • Muscle Weakness / etiology*
  • Muscle Weakness / pathology
  • Muscle Weakness / prevention & control*
  • Neuromuscular Agents / pharmacology*
  • Organ Size
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Sepsis / complications*
  • Valerates / pharmacology*
  • eIF-2 Kinase / metabolism

Substances

  • Lipopolysaccharides
  • Neuromuscular Agents
  • Valerates
  • beta-hydroxyisovaleric acid
  • eIF-2 Kinase
  • Calpain
  • Casp3 protein, mouse
  • Caspase 3
  • Proteasome Endopeptidase Complex