Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure

Daniel E. Forman, Karla M. Daniels, Lawrence P Cahalin, Alexandra Zavin, Kelly Allsup, Peirang Cao, Mahalakshmi Santhanam, Jacob Joseph, Ross Arena, Antonio Lazzari, P. Christian Schulze, Stewart H. Lecker

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. Methods Systolic HF patients (left ventricular ejection fraction [LVEF] ≠40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. Results 54 male patients (66.6 ;plusmn; 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ;plusmn; 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ;plusmn; 6.2 vs 5.0 ;plusmn; 3.5, 6.5 ;plusmn; 4.3 vs 4.3 ;plusmn; 2.8 relative units, respectively; P ≠;.05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P <.05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1β, and IL-6 were similar in HF and control. Conclusion Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

Original languageEnglish
Pages (from-to)422-430
Number of pages9
JournalJournal of Cardiac Failure
Volume20
Issue number6
DOIs
StatePublished - Jan 1 2014

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Systolic Heart Failure
Skeletal Muscle
Heart Failure
Atrophy
Gene Expression
Somatomedins
Ubiquitin
Stroke Volume
Lymphotoxin-beta
Genes
Muscular Atrophy
Quadriceps Muscle
Interleukin-1
C-Reactive Protein
Real-Time Polymerase Chain Reaction
Interleukin-6
Leg
Exercise
Biopsy
Muscles

Keywords

  • gene expression
  • Heart failure
  • skeletal muscle

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure. / Forman, Daniel E.; Daniels, Karla M.; Cahalin, Lawrence P; Zavin, Alexandra; Allsup, Kelly; Cao, Peirang; Santhanam, Mahalakshmi; Joseph, Jacob; Arena, Ross; Lazzari, Antonio; Schulze, P. Christian; Lecker, Stewart H.

In: Journal of Cardiac Failure, Vol. 20, No. 6, 01.01.2014, p. 422-430.

Research output: Contribution to journalArticle

Forman, DE, Daniels, KM, Cahalin, LP, Zavin, A, Allsup, K, Cao, P, Santhanam, M, Joseph, J, Arena, R, Lazzari, A, Schulze, PC & Lecker, SH 2014, 'Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure', Journal of Cardiac Failure, vol. 20, no. 6, pp. 422-430. https://doi.org/10.1016/j.cardfail.2014.03.007
Forman, Daniel E. ; Daniels, Karla M. ; Cahalin, Lawrence P ; Zavin, Alexandra ; Allsup, Kelly ; Cao, Peirang ; Santhanam, Mahalakshmi ; Joseph, Jacob ; Arena, Ross ; Lazzari, Antonio ; Schulze, P. Christian ; Lecker, Stewart H. / Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure. In: Journal of Cardiac Failure. 2014 ; Vol. 20, No. 6. pp. 422-430.
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abstract = "Background Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. Methods Systolic HF patients (left ventricular ejection fraction [LVEF] {\^a}‰ 40{\%}) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. Results 54 male patients (66.6 ;plusmn; 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ;plusmn; 7.8{\%}) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ;plusmn; 6.2 vs 5.0 ;plusmn; 3.5, 6.5 ;plusmn; 4.3 vs 4.3 ;plusmn; 2.8 relative units, respectively; P {\^a}‰ ;.05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P <.05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1β, and IL-6 were similar in HF and control. Conclusion Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.",
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AU - Forman, Daniel E.

AU - Daniels, Karla M.

AU - Cahalin, Lawrence P

AU - Zavin, Alexandra

AU - Allsup, Kelly

AU - Cao, Peirang

AU - Santhanam, Mahalakshmi

AU - Joseph, Jacob

AU - Arena, Ross

AU - Lazzari, Antonio

AU - Schulze, P. Christian

AU - Lecker, Stewart H.

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N2 - Background Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. Methods Systolic HF patients (left ventricular ejection fraction [LVEF] ≠40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. Results 54 male patients (66.6 ;plusmn; 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ;plusmn; 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ;plusmn; 6.2 vs 5.0 ;plusmn; 3.5, 6.5 ;plusmn; 4.3 vs 4.3 ;plusmn; 2.8 relative units, respectively; P ≠;.05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P <.05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1β, and IL-6 were similar in HF and control. Conclusion Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

AB - Background Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. Methods Systolic HF patients (left ventricular ejection fraction [LVEF] ≠40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. Results 54 male patients (66.6 ;plusmn; 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ;plusmn; 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ;plusmn; 6.2 vs 5.0 ;plusmn; 3.5, 6.5 ;plusmn; 4.3 vs 4.3 ;plusmn; 2.8 relative units, respectively; P ≠;.05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P <.05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1β, and IL-6 were similar in HF and control. Conclusion Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

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