Induction of Cachexia in Mice by Systemically Administered Myostatin

SummaryAbnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However, the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here, we show that myostatin (Mstn) is a pro‐oxidant and signals the generation of ROS in muscle cells. Myostatin, a transforming growth factor‐β (TGF‐β) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through tumor necrosis factor‐α (TNF‐α) signaling via NF‐κB and NADPH oxidase. Aged Mstn null (Mstn−/−) muscles, which display reduced sarcopenia, also show an increased basal antioxidant enzyme (AOE) levels and lower NF‐κB levels indicating efficient scavenging of excess ROS. Additionally, our results indicate that both TNF‐α and hydrogen peroxide (H2O2) are potent inducers of Mstn and require NF‐κB signaling for Mstn induction. These results demonstrate that Mstn and TNF‐α are components of a feed forward loop in which Mstn triggers the generation of second messenger ROS, mediated by TNF‐α and NADPH oxidase, and the elevated TNF‐α in turn stimulates Mstn expression. Higher levels of Mstn in turn induce muscle wasting by activating proteasomal‐mediated catabolism of intracellular proteins. Thus, we propose that inhibition of ROS induced by Mstn could lead to reduced muscle wasting during sarcopenia.

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“…, 2000; Langley et al. , 2002) and overexpression of Mstn in vivo results in cachexia in mice (Zimmers et al. , 2002; Reisz‐Porszasz et al.…”

Section: Introductionmentioning

confidence: 99%

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

et al. 2011

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“…Myostatin has both paracrine and endocrine effects (Zimmers et al. 2002), although it is the endocrine function which appears key for regulation of muscle mass, due to an observed inverse correlation with muscle mass in humans (Gonzalez‐Cadavid et al. 1998).…”

Section: Introductionmentioning

confidence: 99%

Lifelong exercise, but not short-term high-intensity interval training, increases GDF11, a marker of successful aging: a preliminary investigation

et al. 2017

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Lifelong exercise is associated with regulation of skeletal mass and function, reductions in frailty, and successful aging. Yet, the influence of exercise on myostatin and myostatin‐interacting factors is relatively under examined in older males. Therefore, we investigated whether serum total myostatin, free myostatin, follistatin, and growth and differentiation factor 11 (GDF11) were altered following high‐intensity interval training (HIIT) in a group of 13 lifelong sedentary (SED; 64 [6] years) and 11 lifelong exercising (LEX; 62 [6] years) older males. SED follistatin was moderately greater than LEX pre‐HIIT (Cohen's d = 0.66), and was largely greater post‐HIIT (Cohen's d = 1.22). The HIIT‐induced increase in follistatin was large in SED (Cohen's d = 0.82) and absent in LEX (Cohen's d = 0.03). GDF11 was higher in LEX pre‐HIIT (Cohen's d = 0.49) and post‐HIIT (Cohen's d = 0.63) compared to SED. HIIT resulted in no change to GDF11 in LEX or SED (Cohen's d = 0.00–0.03). Peak power output and GDF11 were correlated (r = 0.603), independent of grouping. Differences in GDF11 with lifelong exercise training, paired with the correlation between GDF11 and peak power output, suggested that GDF11 may be a relevant myostatin‐interacting peptide to successful aging in humans, and strategies to maintain this need to be further explored.

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“…For example, the authors, using healthy university students, showed significantly increased levels of myostatin mRNA in muscle tissue after the unilateral suspension of a hindlimb for two weeks. In addition, administration of myostatin in vivo to adult mice induceed profound muscle loss analogous to that seen in human cachexia syndrome 117) . Together these studies suggest that increased levels of myostatin lead to muscle wasting.…”

Section: Myostatin -The Other Modulator Of Muscle Regenerationmentioning

confidence: 95%

“…When produced in Chinese hamster ovary cells, the C-terminal dimer remains bound to the N-terminal propeptide (NTPP), which remains in a latent, inactive state 116) . Most, if not all, of the myostatin protein that circulates in blood, also appears to exist in an inactive complex with a variety of proteins, including propeptides 117) .…”

Section: Myostatin -The Other Modulator Of Muscle Regenerationmentioning

confidence: 99%

“…The latent form of myostatin seems to be activated in vitro by dissociating the complex with either acid or heat treatment 116,117) or by proteplytic cleavage of a propeptide Myosin-actin interaction, by mechanical loading, activates STARS/MRTF-A/SRF signaling 74) . Charvet et al 84) proposed that SRF-dependent signaling regulates muscle regeneration by promoting myogenic differentiation, probably due to the induction of IGF-I and IL-4 expression.…”

Section: Myostatin -The Other Modulator Of Muscle Regenerationmentioning

confidence: 99%

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Recent research developments in regeneration of skeletal muscle

Sakuma

Yamaguchi

2012

JPFSM

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Over the last decade, extensive progress has been made with regard to our understanding of the molecules that regulate skeletal muscle regeneration. Satellite cells are musclespecific stem cells located under the basal lamina of muscle fibers, which are responsible for muscle regeneration. This precise coordination of complex stem cell responses throughout adult life is regulated by evolutionarily conserved signaling networks that cooperatively direct and control. This process includes the activation, proliferation, and differentiation of stem cells. This highly regulated process of tissue regeneration recapitulates embryonic organogenesis with respect to the involvement of interactive signal transduction networks. Indeed, various modulators such as insulin-like growth factor-I (IGF-I), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) have been shown to stimulate the activation and proliferation of satellite cells. PI3K (phosphatidylinositol 3-kinase)/Akt/mTOR (mammalian target of rapamycin), calcineurin, and serum response factor (SRF) seem to contribute to muscle regeneration by regulating differentiation of satellite cells. In contrast, myostatin inhibits these processes through forkhead box O (FOXO) and/or SMAD 2/3-dependent signaling. In this review, the recent findings for muscle regeneration are described.

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Induction of Cachexia in Mice by Systemically Administered Myostatin

Cited by 818 publications

References 28 publications

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

Lifelong exercise, but not short-term high-intensity interval training, increases GDF11, a marker of successful aging: a preliminary investigation

Recent research developments in regeneration of skeletal muscle

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