J Appl Physiol 110: 869–870, 2011;
doi:10.1152/japplphysiol.00072.2011.
Invited Editorial
Does a reduction in anabolic signaling contribute to muscle wasting in
chronic heart failure?
Kyle L. Timmerman2,3 and Blake B. Rasmussen1,2,3
Department of 1Physical Therapy and Division of 2Rehabilitation Sciences, 3Sealy Center on Aging, University of Texas
Medical Branch, Galveston, Texas
Address for reprint requests and other correspondence: B. B. Rasmussen,
Univ. of Texas Medical Branch, Dept. of Physical Therapy, Div. of Rehabilitation Sciences, Sealy Center on Aging, 301 Univ. Blvd., Galveston, TX
77555-1144 (e-mail: [email protected]).
http://www.jap.org
muscle protein synthesis. Unfortunately, the authors were unable to detect a signal for Akt phosphorylation at Thr308, but
the authors did measure a number of downstream targets of this
phosphorylation site, including mTOR and glycogen synthase
kinase-3␤ (GSK-3␤). Phosphorylation of mTOR stimulates
protein translation via the downstream regulation of p70 ribosomal S6 kinase 1 (S6K1) and eukaryotic translation initiation
factor 4E binding protein-1 (4E-BP1), while GSK-3␤ activates
translation via the inhibition of eukaryotic initiation factor 2B
(eIF2B). mTOR, S6K1, and 4E-BP1 phosphorylation tended to
be lower in CHF patients but did not reach statistical significance. There was no difference between groups for GSK-3␤
phosphorylation. One likely explanation for why the authors
report a significant reduction in Akt Ser473 phosphorylation
(but only a nonsignificant trend for lower mTOR and S6K1
phosphorylation and no differences in IGF-1 expression) is the
careful matching of the control subjects for age, muscle mass,
Fig. 1. A: diagram highlighting the changes in the Akt/mammalian target of
rapamycin (mTOR) signaling pathway as reported by Toth et al. (17). The
authors found that chronic heart failure (CHF) patients had significantly
reduced basal Akt (Ser473) phosphorylation compared with healthy controls.
Groups were matched for age, muscle mass, and physical activity. Phosphorylation of Akt (Ser473) was related to muscle myosin protein content and knee
extensor isometric torque in the CHF subjects. mTOR and S6K1 phosphorylation tended to be lower in CHF compared with control subjects but did not
reach significance; however, Toth et al. have previously shown that basal rates
of muscle protein synthesis are not different between healthy controls and CHF
(16). The authors propose that alterations in basal Akt signaling may promote
muscle loss in CHF. B: basal differences in muscle anabolic signaling and
protein synthesis are also difficult to detect in age-related sarcopenia but
become readily apparent when exposed to an anabolic stimulus such as
essential amino acids, insulin, or exercise. Based on this information and
coupled with the new information reported by Toth et al. (17), we propose a
similar (but hypothetical) impaired response to an anabolic stimulus in CHF
patients.
8750-7587/11 Copyright © 2011 the American Physiological Society
869
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CHRONIC HEART FAILURE (CHF) is a complex and prevalent
disease affecting 2% of adults in developed countries. This
number increases to 6 –10% in adults over the age of 65 (3, 8),
and on diagnosis, half of all CHF patients die within 4 years
(11). In addition to the significant increase in mortality risk,
CHF patients experience substantial declines in physical and
mental health, the ability to perform activities of daily living,
and, subsequently, have a decreased quality of life (6). A
common comorbidity of CHF is the loss of metabolically
active lean tissue, known as cardiac cachexia. Cachexia is not
unique to CHF. Loss of skeletal muscle occurs with aging and
is prevalent in AIDS, cancer, sepsis, and other chronic diseases. Depending on how cachexia is defined, this condition
has been found in up to 50% of CHF patients, which is an
important concern as the development of cardiac cachexia
significantly increases risk of mortality (2, 6). Skeletal muscle
mass increases or decreases depending on the balance between
anabolic and catabolic stimuli, and the net muscle protein
balance is influenced by a number of extrinsic and intrinsic
factors, including Akt-mediated mammalian target of rapamycin (mTOR) signaling. For instance, phosphorylation of Akt
(Ser473) is an upstream positive regulator of mTOR (an
important pathway in the regulation of translation initiation and
overall muscle size), but it also controls muscle protein breakdown by preventing the nuclear translocation of forkhead box
O (FOXO) transcription factors, which facilitates ubiquitin
ligase-mediated proteolysis (12). However, while CHF is not
associated with any alterations in the FOXO-regulated genes
atrogin and MuRF1 (9), it has previously been reported that
CHF is associated with decreased expression of insulin-like
growth factor-1 (IGF-1), a key upstream regulator of Akt
signaling (1). Thus it is plausible that altered Akt/mTOR
signaling may underlie CHF-related muscle loss, and by extension, the development of cardiac cachexia.
In this issue of the Journal of Applied Physiology, Toth and
colleagues (17) provide novel data showing that basal Akt
phosphorylation is decreased in CHF patients compared with
healthy age- and physical activity-matched controls. Specifically, phosphorylation of Akt at Ser473 relative to total Akt
protein expression (pAkt/Akt) was lower in CHF patients
compared with control subjects, and positively correlated with
myosin protein content. However, IGF-1 mRNA expression
was not different between groups. The decreased phosphorylation of the Akt Ser473 site is indicative of decreased Akt
activation, which the authors speculate may influence the
downstream regulation of translation initiation and the rate of
Invited Editorial
870
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
J Appl Physiol • VOL
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and physical activity. Previous studies did not account for
muscle disuse (a common trait in CHF patients), but this is
essential, as conditions associated with physical inactivity can
reduce total Akt content and mTOR signaling in skeletal
muscle (4). Another possibility is that the present study is
insufficiently powered to detect group differences in a number
of the variables measured. However, detecting differences in
protein phosphorylation can be difficult in the basal, fasting
condition. On the other hand, it may be more likely to detect
group differences under anabolic conditions such as feeding
and exercise. Overall, the findings of this study are essentially
limited to the group difference reported in Akt (Ser473) phosphorylation. The difference in basal Akt phosphorylation between CHF patients and healthy controls is interesting and does
provide preliminary evidence that muscle anabolic signaling
appears to be reduced in CHF. However, given the absence of
significant group differences in the phosphorylation of Aktassociated signaling proteins, it will be important for future
studies to establish the precise role of reduced basal Akt
signaling in the development of cardiac cachexia.
The loss of lean mass concomitant with CHF significantly
worsens quality of life and mortality risk in CHF patients (2,
6), and uncovering the mechanisms underlying the development of cardiac cachexia is an important area of future research. The study by Toth et al. (17) represents an important
first step toward identifying the cellular mechanisms that may
contribute to, or serve as molecular biomarkers for the onset of
this condition. It should be pointed out that in the fasted state
(as the subjects were in the present study) muscle protein
breakdown exceeds muscle protein synthesis, resulting in overall catabolism (i.e., net negative protein balance). This, however, is only half of the story, as skeletal muscle fluctuates
between periods of positive and negative net balance throughout the day depending primarily on feeding and activity status.
A logical “next step” toward increasing our understanding of
the molecular events that may influence CHF-related muscle
loss is to focus on the influence of anabolic stimuli (e.g.,
feeding) in CHF patients as this may improve the ability to
detect differences in anabolic signaling. For instance, when
comparing healthy elderly and young subjects, basal muscle
protein synthesis and Akt-mTOR signaling are essentially
equivalent (5). However, recent studies have shown age-related
differences in the response to anabolic stimuli such as exercise
(5, 13), nutrition (7, 18), and insulin administration (10, 14,
15). Consequently, it has been proposed that an inadequate
response to anabolic stimuli, rather than any intrinsic basal
differences, may significantly contribute to age-related muscle
loss (sarcopenia). It is reasonable to speculate that a reduced
ability to respond to anabolic stimuli may also play a key role
in CHF-related muscle loss (Fig. 1). Toth et al. (17) have
provided good evidence of reduced anabolic signaling in skeletal muscle from fasted CHF patients, and it will be interesting
to see if future studies in CHF patients also demonstrate an
inability to respond to anabolic stimuli as detected in agerelated sarcopenia.