title: Age associated decline in the conversion of leucine to β-Hydroxy-β-Methylbutyrate in rats.
abstract: The loss of muscle mass is considered to be a major factor contributing to strength decline during aging. β-Hydroxy-β-Methylbutyrate (HMB), a metabolite of leucine has been shown to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. However, the production and regulation of endogenous levels of HMB over the lifespan have not been investigated.
  
  
  
  The objective of the present study was to do a cross-sectional analysis of the basal plasma levels of HMB in male Sprague-Dawley rats of different ages and to compare the efficiency of conversion of leucine to HMB in young versus older rats.
  
  
  
  Plasma levels of HMB and α-ketoisocaproate (KIC) were analyzed in rats of different age groups (3, 9, 12 and 24months old, n=10 per group). Levels of 4-HPPD, the enzyme involved in the conversion of KIC to HMB in the liver were determined by ELISA. The conversion efficiency of leucine to HMB was compared between 3 and 24month rats after an oral bolus dose of leucine.
  
  
  
  Endogenous circulating levels of HMB were significantly reduced in older age rats compared to young rats (100±3.7 vs 156±10 (mean±SEM), ng/mL, p<0.001). A significant negative correlation was seen between HMB levels and age. The liver levels of 4-HPPD were found to be significantly lower in old versus young rats. Consistent with this, the conversion efficiency of leucine to HMB was significantly lower in the aged versus young cohorts.
  
  
  
  In summary, this study depicts for the first time that the basal levels of HMB, a metabolite of amino acid leucine, declines with age, and that this decline is due to perturbations in the key enzyme 4-HPPD which catalyzes the conversion of KIC to HMB. As a consequence, the efficiency of conversion of leucine to HMB is diminished in older rats compared to younger rats.
authors.affiliation: Abbott Nutrition Research and Development, 20 Biopolis Way, Singapore 138668. Electronic address: shreeram.sathya@abbott.com.
authors.forename: Sathyavageeswaran
authors.initials: S
authors.lastname: Shreeram
authors.affiliation: Syngene International Limited, Biocon Park, Plot 2 & 3 Bommasandra 4th Phase, Jigani Link Road, Bangalore 560099, India.
authors.forename: Subbarayan
authors.initials: S
authors.lastname: Ramesh
authors.affiliation: Syngene International Limited, Biocon Park, Plot 2 & 3 Bommasandra 4th Phase, Jigani Link Road, Bangalore 560099, India.
authors.forename: Jithesh K
authors.initials: JK
authors.lastname: Puthan
authors.affiliation: Syngene International Limited, Biocon Park, Plot 2 & 3 Bommasandra 4th Phase, Jigani Link Road, Bangalore 560099, India.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balakrishnan
authors.affiliation: Syngene International Limited, Biocon Park, Plot 2 & 3 Bommasandra 4th Phase, Jigani Link Road, Bangalore 560099, India.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Abbott Nutrition Research and Development, 3300 Stelzer Road, Columbus, OH 43219, USA.
authors.forename: Murali Todime
authors.initials: MT
authors.lastname: Reddy
authors.affiliation: Abbott Nutrition Research and Development, 3300 Stelzer Road, Columbus, OH 43219, USA.
authors.forename: Suzette L
authors.initials: SL
authors.lastname: Pereira
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D019587:Dietary Supplements; D006801:Humans; D007651:Keto Acids / Q000097:blood*; D007930:Leucine / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014631:Valerates / Q000097:blood*
chemical_list: D007651:Keto Acids; D014631:Valerates; C004961:beta-hydroxyisovaleric acid; C013082:alpha-ketoisocaproic acid; D015111:4-Hydroxyphenylpyruvate Dioxygenase; D007930:Leucine
keywords: 4-HPPD; Aging; Ketoisocaproate dioxygenase; Leucine; Plasma levels; Rats; β-Hydroxy β-Methylbutyrate