Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

Breitbart, Astrid; Auger‐Messier, Mannix; Molkentin, Jeffery D.; Heineke, Joerg

doi:10.1152/ajpheart.00200.2011

Cited by 107 publications

(79 citation statements)

References 101 publications

(137 reference statements)

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“…Although Myostatin is doubtless an inhibitor of skeletal muscle mass development, its role in muscle atrophy remains unclear. Indeed, in contrast to early observations highlighting a link between elevated levels of Mstn and low muscularity situations,41, 42, 43 recent studies showed a decrease of circulating Myostatin in conditions characterized by reduced skeletal muscle mass such as ageing, but without correlation between Myostatin levels and muscle mass 44, 45, 46. In agreement with our results, Breitbart et al .…”

Section: Discussionsupporting

confidence: 90%

Circulating Activin A predicts survival in cancer patients

Loumaye

Barsy

Nachit

et al. 2017

J cachexia sarcopenia muscle

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BackgroundSeveral experimental evidences pinpoint the possible role of Activin A (ActA) as a driver of cancer cachexia. Supporting this hypothesis, we showed recently that human cancer cachexia is associated with high ActA levels. Moreover, ActA levels were correlated with body weight loss and skeletal muscle density, two prognostic factors in cancer patients. Our goal was therefore to investigate the value of ActA to predict survival in cancer patients.MethodsPatients with colorectal or lung cancer were prospectively enrolled at the time of diagnosis or relapse between January 2012 and March 2014. At baseline, patients had clinical, nutritional, and functional assessment. Body composition and skeletal muscle density were measured by CT scan, and plasma ActA concentrations were determined. Overall survival (OS) was analysed since inclusion to 24 months later.ResultsSurvival data were available for 149 patients out of 152. Patients with high ActA (≥408 pg/mL) had lower OS than those with low levels, regardless the type of cancer (OS in colorectal cancer, 50% vs. 79%, P < 0.05; and in lung cancer, 27% vs. 67%, P = 0.001). The multivariable analysis confirmed the prognostic value of ActA independently of tumour stage or inflammatory markers, particularly in lung cancer. Low muscularity was also an independent prognostic factor.ConclusionsOur study demonstrates that high ActA level is an independent prognosis factor of survival in cancer patients. More than a basic marker of the severity of the neoplastic disease or of the inflammatory process, ActA seems to influence survival by contributing to the development of cachexia and loss of skeletal muscle mass.

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Section: Discussionsupporting

confidence: 90%

Circulating Activin A predicts survival in cancer patients

Loumaye

Barsy

Nachit

et al. 2017

J cachexia sarcopenia muscle

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“…Proteolytic processing, secretion, proteolytic activation and inhibitory proteins (e.g. follistatin) can affect the activity of Mstn and other transforming growth factor- (TGF) factors (reviewed by Breitbart et al, 2011;Moustakas and Heldin, 2009). Moreover, TGF signaling is downregulated by inhibitory Smad, protein phosphatases and ubiquitin-dependent degradation of TGF receptors and Smads (reviewed by Liu and Feng, 2010).…”

Section: Discussionmentioning

confidence: 99%

Rheb, an activator of target of rapamycin, in the blackback land crab,Gecarcinus lateralis: cloning and effects of molting and unweighting on expression in skeletal muscle

MacLea

Abuhagr

Pitts

et al. 2012

Journal of Experimental Biology

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SUMMARY Molt-induced claw muscle atrophy in decapod crustaceans facilitates exuviation and is coordinated by ecdysteroid hormones. There is a 4-fold reduction in mass accompanied by remodeling of the contractile apparatus, which is associated with an 11-fold increase in myofibrillar protein synthesis by the end of the premolt period. Loss of a walking limb or claw causes a loss of mass in the associated thoracic musculature; this unweighting atrophy occurs in intermolt and is ecdysteroid independent. Myostatin (Mstn) is a negative regulator of muscle growth in mammals; it suppresses protein synthesis, in part, by inhibiting the insulin/metazoan target of rapamycin (mTOR) signaling pathway. Signaling via mTOR activates translation by phosphorylating ribosomal S6 kinase (s6k) and 4E-binding protein 1. Rheb (Ras homolog enriched in brain), a GTP-binding protein, is a key activator of mTOR and is inhibited by Rheb-GTPase-activating protein (GAP). Akt protein kinase inactivates Rheb-GAP, thus slowing Rheb-GTPase activity and maintaining mTOR in the active state. We hypothesized that the large increase in global protein synthesis in claw muscle was due to regulation of mTOR activity by ecdysteroids, caused either directly or indirectly via Mstn. In the blackback land crab, Gecarcinus lateralis, a Mstn-like gene (Gl-Mstn) is downregulated as much as 17-fold in claw muscle during premolt and upregulated 3-fold in unweighted thoracic muscle during intermolt. Gl-Mstn expression in claw muscle is negatively correlated with hemolymph ecdysteroid level. Full-length cDNAs encoding Rheb orthologs from three crustacean species (G. lateralis, Carcinus maenas and Homarus americanus), as well as partial cDNAs encoding Akt (Gl-Akt), mTOR (Gl-mTOR) and s6k (Gl-s6k) from G. lateralis, were cloned. The effects of molting on insulin/mTOR signaling components were quantified in claw closer, weighted thoracic and unweighted thoracic muscles using quantitative polymerase chain reaction. Gl-Rheb mRNA levels increased 3.4-fold and 3.9-fold during premolt in claw muscles from animals induced to molt by eyestalk ablation (ESA) and multiple leg autotomy (MLA), respectively, and mRNA levels were positively correlated with hemolymph ecdysteroids. There was little or no effect of molting on Gl-Rheb expression in weighted thoracic muscle and no correlation of Gl-Rheb mRNA with ecdysteroid titer. There were significant changes in Gl-Akt, Gl-mTOR and Gl-s6k expression with molt stage. These changes were transient and were not correlated with hemolymph ecdysteroids. The two muscles differed in terms of the relationship between Gl-Rheb and Gl-Mstn expression. In thoracic muscle, Gl-Rheb mRNA was positively correlated with Gl-Mstn mRNA in both ESA and MLA animals. By contrast, Gl-Rheb mRNA in claw muscle was negatively correlated with Gl-Mstn mRNA in ESA animals, and no correlation was observed in MLA animals. Unweighting increased Gl-Rheb expression in thoracic muscle at all molt stages; the greatest difference (2.2-fold) was observed in intermolt animals. There was also a 1.3-fold increase in Gl-s6k mRNA level in unweighted thoracic muscle. These data indicate that the mTOR pathway is upregulated in atrophic muscles. Gl-Rheb, in particular, appears to play a role in the molt-induced increase in protein synthesis in the claw muscle.

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“…During pathological loading of the heart, the myocardium produces and secretes myostatin into circulation where it reaches skeletal muscles and inhibits their growth. 32 We have observed in heart failure rats that muscle atrophy was combined with changes in myostatin/follistatin expression. 22,33 Muscle disuse by bed rest can also contribute to protein catabolism.…”

Section: Imbalance Between Anabolic and Catabolic Processesmentioning

confidence: 95%

Cardiac cachexia and muscle wasting: definition, physiopathology, and clinical consequences

Okoshi¹,

Romeiro²,

Martínez³

et al. 2014

RRCC

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Cachexia and muscle wasting are frequently observed in heart failure patients. Cachexia is a predictor of reduced survival, independent of important parameters such as age, heart failure functional class, and functional capacity. Muscle and fat wasting can also predict adverse outcome during cardiac failure. Only more recently were these conditions defined in International Consensus. Considering that heart failure is an inflammatory disease, cardiac cachexia has been diagnosed by finding a body weight loss .5%, in the absence of other diseases and independent of other criteria. Muscle wasting has been defined as lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean for healthy individuals between 20 years and 30 years old from the same ethnic group. The etiology of heart failure-associated cachexia and muscle wasting is multifactorial, and the underlying physiopathological mechanisms are not completely understood. The most important factors are reduced food intake, gastrointestinal alterations, immunological activation, neurohormonal abnormalities, and an imbalance between anabolic and catabolic processes. Cachexia and muscle wasting have clinical consequences in several organs and systems including the gastrointestinal and erythropoietic systems, and the heart, previously affected by the primary disease. We hope that a better understanding of the mechanisms involved in their physiopathology will allow the development of pharmacological and nonpharmacological therapies to effectively prevent and treat heart failure-induced cachexia and muscle wasting before significant body weight and muscle wasting occurs.

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Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

Cited by 107 publications

References 101 publications

Circulating Activin A predicts survival in cancer patients

Circulating Activin A predicts survival in cancer patients

Rheb, an activator of target of rapamycin, in the blackback land crab,Gecarcinus lateralis: cloning and effects of molting and unweighting on expression in skeletal muscle

Cardiac cachexia and muscle wasting: definition, physiopathology, and clinical consequences

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