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.

Materials and 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.

Conclusion: 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.

Keywords: IGF1 and IGFBP-5; hybrid fibers; muscle quality.

Figure 1

Representative MHC single muscle fiber silver-stained SDS–PAGE from a heart failure patient. Notes: Lanes 1 and 7 represent a hybrid isoform that coexpresses both MHC IIx and MHC IIa; lanes 2, 4, and 8 represent MHC IIa; and lanes 3, 5, and 6 represent MHC I isoforms. Abbreviations: MHC, myosin heavy chain; SDS–PAGE, sodium dodecyl sulfate– polyacrylamide gel electrophoresis.

Figure 2

Whole-muscle CSA and insulin-like growth factor-1 mRNA expression in heart failure patients. Notes: Pearson product-moment correlation coefficient was used to describe the linear relationship. This relationship was highly correlated at r = 0.931 (P < 0.05). Abbreviations: IGF-1, insulin-like growth factor-1; CSA, cross-sectional area.

Figure 3

The melt-curve analysis for IGF-1 and β-actin. Note: The curve to the left represents IGF-I and the curve to the right represents the β-actin. Abbreviation: IGF-1, insulin-like growth factor-1.