title: Skeletal muscle molecular alterations precede whole-muscle dysfunction in NYHA Class II heart failure patients.
abstract: BACKGROUND
  Heart failure (HF), a debilitating disease in a growing number of adults, exerts structural and neurohormonal changes in both cardiac and skeletal muscles. However, these alterations and their affected molecular pathways remain uncharacterized. Disease progression is known to transform skeletal muscle fiber composition by unknown mechanisms. In addition, perturbation of specific hormonal pathways, including those involving skeletal muscle insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-5 (IGFB-5) appears to occur, likely affecting muscle metabolism and regeneration. We hypothesized that changes in IGF-1 and IGFB-5 mRNA levels correlate with the transformation of single-skeletal muscle fiber myosin heavy chain isoforms early in disease progression, making these molecules valuable markers of skeletal muscle changes in heart failure.
  
  
  METHODS
  To investigate these molecules during "early" events in HF patients, we obtained skeletal muscle biopsies from New York Heart Association (NYHA) Class II HF patients and controls for molecular analyses of single fibers, and we also quantified isometric strength and muscle size.
  
  
  RESULTS
  There were more (P < 0.05) single muscle fibers coexpressing two or more myosin heavy chains in the HF patients (30% ± 7%) compared to the control subjects (13% ± 2%). IGF-1 and IGFBP-5 expression was fivefold and 15-fold lower in patients with in HF compared to control subjects (P < 0.05), respectively. Strikingly, there was a correlation in IGF-1 expression and muscle cross-sectional area (P < 0.05) resulting in a decrease in whole-muscle quality (P < 0.05) in the HF patients, despite no significant decrease in isometric strength or whole-muscle size.
  
  
  CONCLUSIONS
  These data indicate that molecular alterations in myosin heavy chain isoforms, IGF-1, and IGFB-5 levels precede the gross morphological and functional deficits that have previously been associated with HF, and may be used as a predictor of functional outcome in patients.
authors.affiliation: Department of Nutrition and Kinesiology, University of Central Missouri, Warrensburg, MO 64093, USA. godard@ucmo.edu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Godard
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Whitman
authors.forename: Yao-Hua
authors.initials: YH
authors.lastname: Song
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
mesh_terms: D000368:Aged; D001707:Biopsy, Needle; D015444:Exercise; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000503:physiopathology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D018975:Insulin-Like Growth Factor Binding Protein 5; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D018995:Myosin Heavy Chains