Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure.
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 ± 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ± 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 ± 6.2 vs 5.0 ± 3.5, 6.5 ± 4.3 vs 4.3 ± 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.


CONCLUSIONS
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.
New England Geriatric Research, Education, and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts; Division of Cardiovascular Medicine, Veterans Affairs Boston Healthcare System, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical, School, Boston, Massachusetts. Electronic address: deforman@partners.org.
Daniel E
DE
Forman
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical, School, Boston, Massachusetts.
Karla M
KM
Daniels
Department of Physical Therapy, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida.
Lawrence P
LP
Cahalin
New England Geriatric Research, Education, and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts.
Alexandra
A
Zavin
New England Geriatric Research, Education, and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts.
Kelly
K
Allsup
Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Peirang
P
Cao
Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Mahalakshmi
M
Santhanam
Division of Cardiovascular Medicine, Veterans Affairs Boston Healthcare System, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical, School, Boston, Massachusetts.
Jacob
J
Joseph
Department of Physical Therapy and Integrative Physiology Laboratory - College of Applied Health Sciences, University of Illinois Chicago, Chicago, Illinois.
Ross
R
Arena
Division of Rheumatology, Veterans Affairs Boston Healthcare System, Boston, Massachusetts; Boston University School of Medicine, Boston, Massachusetts.
Antonio
A
Lazzari
Division of Cardiovascular Medicine, Columbia University Medical Center, New York, New York.
P Christian
PC
Schulze
Boston University School of Medicine, Boston, Massachusetts.
Stewart H
SH
Lecker
D000368:Aged; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005080:Exercise Test / Q000379:methods*; D005786:Gene Expression Regulation; D054143:Heart Failure, Systolic / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D006787:Hospitals, Veterans; D006801:Humans; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D013318:Stroke Volume / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology
Heart failure; gene expression; skeletal muscle