Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure

Rocco Barazzoni; Gianluca Gortan Cappellari; Sandra Palus; Pierandrea Vinci; Giulia Ruozi; Michela Zanetti; Annamaria Semolic; Nicole Ebner; Stephan von Haehling; Gianfranco Sinagra; Mauro Giacca; Jochen Springer

doi:10.1002/jcsm.12254

Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure

Rocco Barazzoni^*, Gianluca Gortan Cappellari, Sandra Palus, Pierandrea Vinci, Giulia Ruozi, Michela Zanetti, Annamaria Semolic, Nicole Ebner, Stephan von Haehling, Gianfranco Sinagra, Mauro Giacca, Jochen Springer

^*Corresponding author for this work

Cardiovascular Medicine & Sciences

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

Abstract

Background: Chronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models. Methods: We investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post-myocardial infarction CHF model. Results: No statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham-operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level (P < 0.05), associated with activating nuclear translocation of pro-inflammatory transcription factor nuclear factor-κB. AG completely normalized all alterations (P < 0.05 vs P, P = NS vs sham-operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG-dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group. Conclusions: Sustained peripheral AG treatment with preserved food intake normalizes a CHF-induced tissue-specific cluster of skeletal muscle mitochondrial dysfunction, pro-inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF-associated muscle catabolic alterations, with potential positive impact on patient outcome.

Original language	English
Pages (from-to)	991-998
Number of pages	8
Journal	Journal of Cachexia, Sarcopenia and Muscle
Volume	8
Issue number	6
DOIs	https://doi.org/10.1002/jcsm.12254
Publication status	Published - 1 Dec 2017

Keywords

Ghrelin
Insulin signalling
Mitochondria
Skeletal muscle

Access to Document

10.1002/jcsm.12254

Cite this

Barazzoni, R., Gortan Cappellari, G., Palus, S., Vinci, P., Ruozi, G., Zanetti, M., Semolic, A., Ebner, N., von Haehling, S., Sinagra, G., Giacca, M., & Springer, J. (2017). Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure. Journal of Cachexia, Sarcopenia and Muscle, 8(6), 991-998. https://doi.org/10.1002/jcsm.12254

@article{976d0695592b4ff491a2e09a8cd251f7,

title = "Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure",

abstract = "Background: Chronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models. Methods: We investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post-myocardial infarction CHF model. Results: No statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham-operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level (P < 0.05), associated with activating nuclear translocation of pro-inflammatory transcription factor nuclear factor-κB. AG completely normalized all alterations (P < 0.05 vs P, P = NS vs sham-operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG-dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group. Conclusions: Sustained peripheral AG treatment with preserved food intake normalizes a CHF-induced tissue-specific cluster of skeletal muscle mitochondrial dysfunction, pro-inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF-associated muscle catabolic alterations, with potential positive impact on patient outcome.",

keywords = "Ghrelin, Insulin signalling, Mitochondria, Skeletal muscle",

author = "Rocco Barazzoni and {Gortan Cappellari}, Gianluca and Sandra Palus and Pierandrea Vinci and Giulia Ruozi and Michela Zanetti and Annamaria Semolic and Nicole Ebner and {von Haehling}, Stephan and Gianfranco Sinagra and Mauro Giacca and Jochen Springer",

year = "2017",

month = dec,

day = "1",

doi = "10.1002/jcsm.12254",

language = "English",

volume = "8",

pages = "991--998",

journal = "Journal of Cachexia, Sarcopenia and Muscle",

issn = "2190-5991",

publisher = "Wiley-Blackwell",

number = "6",

}

Barazzoni, R, Gortan Cappellari, G, Palus, S, Vinci, P, Ruozi, G, Zanetti, M, Semolic, A, Ebner, N, von Haehling, S, Sinagra, G, Giacca, M & Springer, J 2017, 'Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure', Journal of Cachexia, Sarcopenia and Muscle, vol. 8, no. 6, pp. 991-998. https://doi.org/10.1002/jcsm.12254

TY - JOUR

T1 - Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure

AU - Barazzoni, Rocco

AU - Gortan Cappellari, Gianluca

AU - Palus, Sandra

AU - Vinci, Pierandrea

AU - Ruozi, Giulia

AU - Zanetti, Michela

AU - Semolic, Annamaria

AU - Ebner, Nicole

AU - von Haehling, Stephan

AU - Sinagra, Gianfranco

AU - Giacca, Mauro

AU - Springer, Jochen

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background: Chronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models. Methods: We investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post-myocardial infarction CHF model. Results: No statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham-operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level (P < 0.05), associated with activating nuclear translocation of pro-inflammatory transcription factor nuclear factor-κB. AG completely normalized all alterations (P < 0.05 vs P, P = NS vs sham-operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG-dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group. Conclusions: Sustained peripheral AG treatment with preserved food intake normalizes a CHF-induced tissue-specific cluster of skeletal muscle mitochondrial dysfunction, pro-inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF-associated muscle catabolic alterations, with potential positive impact on patient outcome.

AB - Background: Chronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models. Methods: We investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post-myocardial infarction CHF model. Results: No statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham-operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level (P < 0.05), associated with activating nuclear translocation of pro-inflammatory transcription factor nuclear factor-κB. AG completely normalized all alterations (P < 0.05 vs P, P = NS vs sham-operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG-dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group. Conclusions: Sustained peripheral AG treatment with preserved food intake normalizes a CHF-induced tissue-specific cluster of skeletal muscle mitochondrial dysfunction, pro-inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF-associated muscle catabolic alterations, with potential positive impact on patient outcome.

KW - Ghrelin

KW - Insulin signalling

KW - Mitochondria

KW - Skeletal muscle

UR - http://www.scopus.com/inward/record.url?scp=85032983869&partnerID=8YFLogxK

U2 - 10.1002/jcsm.12254

DO - 10.1002/jcsm.12254

M3 - Article

C2 - 29098797

AN - SCOPUS:85032983869

SN - 2190-5991

VL - 8

SP - 991

EP - 998

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

IS - 6

ER -

Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this