Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone

Iskenderian, Andrea; Liu, Nan; Deng, Qingwei; Huang, Yan; Shen, Ching-Hui; Palmieri, Kathleen; Crooker, Robert; Lundberg, Dianna; Kastrapeli, Niksa; Pescatore, Brian; Romashko, Alla; Dumas, John; Comeau, Robert D.; Norton, Angela; Pan, Jing; Rong, Haojing; Derakhchan, Kathy; Ehmann, David E.

doi:10.1186/s13395-018-0180-z

Cited by 41 publications

(54 citation statements)

References 68 publications

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“…are under development in clinical settings. [100][101][102] In addition, an anti-myostatin peptibody that binds myostatin or blocks its receptor is also under development. 18) These data suggest that molecules that block myostatin-ActRIIB signaling would be potentially useful for enhancing muscle growth.…”

Section: Blocking Myostatin-actriib Signalingmentioning

confidence: 99%

Sarcopenia in Chronic Kidney Disease: Factors, Mechanisms, and Therapeutic Interventions

Watanabe

Enoki

Maruyama

2019

Biological & Pharmaceutical Bulletin

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Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and decreased muscle endurance. Many insights into the molecular mechanisms of muscle wasting in CKD have been obtained. A persistent imbalance between protein degradation and synthesis in muscle causes muscle wasting. During muscle wasting, high levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The myostatin binding to its receptor activin A receptor type IIB stimulates the expression of atrogenes such as atrogin-1 and muscle ring factor 1, members of the muscle-specific ubiquitin ligase family. Impaired mitochondrial function also contributes to reducing muscle endurance. The increased protein-bound uremic toxin, parathyroid hormone, glucocorticoid, and angiotensin II levels that are observed in CKD all have a negative effect on muscle mass and endurance. Among the protein-bound uremic toxins, indoxyl sulfate, an indole-containing compound has the potential to induce muscle atrophy by stimulating ROS-mediated myostatin and atrogenes expression. Indoxyl sulfate also impairs mitochondrial function. Some potential therapeutic approaches based on the muscle wasting mechanisms in CKD are currently in the testing stages.

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Section: Blocking Myostatin-actriib Signalingmentioning

confidence: 99%

Sarcopenia in Chronic Kidney Disease: Factors, Mechanisms, and Therapeutic Interventions

Watanabe

Enoki

Maruyama

2019

Biological & Pharmaceutical Bulletin

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“…8 Due to its potential performance enhancing properties, follistatin is prohibited according to the WADA list 2019 (chapter S4 "Hormone and metabolic modulators"). 9 So far, most follistatin administration studies have been performed in mouse models only 8,[10][11][12][13][14] and currently, there is no approved follistatin pharmaceutical available. However, follistatin is accessible on the black market.…”

mentioning

confidence: 99%

“…Five antibodies performed with very low (ab157471, ab64490, ab58920; lanes 2-4) to low recoveries (SAB2100858, SAB1402515; lanes[8][9]. Of the remaining seven antibodies, only three (NBP1-79163, BAF669, ab47942; lanes[11][12][13] showed no cross-reactions with other proteins present (i.e. remaining BSA from Dynabeads, light and heavy chains of antibodies after heating in LDS sample buffer).…”

mentioning

confidence: 99%

Detection of black market follistatin 344

Reichel

Gmeiner

Thevis

2019

Drug Testing and Analysis

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Follistatin, a myostatin‐inhibiting protein, is prohibited according to chapter S4 of the “WADA 2019 List of Prohibited Substances and Methods”. While currently no approved pharmaceutical formulations of follistatin are available, follistatin can be bought on the black market. Most of the products are labeled “follistatin 344” (FS344), a few “follistatin 315”. A study on FS344 black market products was performed and an electrophoretic detection method for serum and urine developed. While only nine of the 17 tested products actually contained follistatin, in some of the others growth promoting peptides were found (e.g. MGF, GHRP‐2). Surprisingly, all nine products contained His‐tagged FS344 and a high degree of its oligomers. The detection method is based on immunomagnetic purification followed by SDS‐PAGE and Western blotting with a monoclonal anti‐His antibody. Alternatively, a monoclonal anti‐follistatin antibody can be used. For immunoprecipitation (IP), a polyclonal anti‐follistatin antibody is applied. An evaluation of suitable antibodies for IP and immunoblotting is also presented. Furthermore, practically all currently available follistatin standards were investigated. The detection limit of the method for black market FS344 in urine is ca 0.1 ng/mL for 10 mL. For a sample volume of 100 μL, an LOD of 5 ng/mL could be achieved for serum. Due to the presence of His‐tags an unambiguous differentiation from endogenous follistatin is possible.

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“…Hence, myostatin antagonism seems like an attractive approach for muscle wasting since myostatin is a secreted protein and acts predominantly on skeletal muscle. Furthermore, application of anti‐myostatin antibody increases muscle mass and improves muscle strength in animal models of Duchenne muscular dystrophy and natural ageing . In particular, a preclinical study by Latres et al .…”

Section: Interventionsmentioning

confidence: 99%

Sarcopenia: Tilting the Balance of Protein Homeostasis

2019

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Sarcopenia, defined as age‐associated decline of muscle mass and function, is a risk factor for mortality and disability, and comorbid with several chronic diseases such as type II diabetes and cardiovascular diseases. Clinical trials showed that nutritional supplements had positive effects on muscle mass, but not on muscle function and strength, demonstrating our limited understanding of the molecular events involved in the ageing muscle. Protein homeostasis, the equilibrium between protein synthesis and degradation, is proposed as the major mechanism underlying the development of sarcopenia. As the key central regulator of protein homeostasis, the mammalian target of rapamycin (mTOR) is proposed to be essential for muscle hypertrophy. Paradoxically, sustained activation of mTOR complex 1 (mTORC1) is associated with a loss of sensitivity to extracellular signaling in the elderly. It is not understood why sustained mTORC1 activity, which should induce muscle hypertrophy, instead results in muscle atrophy. Here, recent findings on the implications of disrupting protein homeostasis on muscle physiology and sarcopenia development in the context of mTOR/protein kinase B (AKT) signaling are reviewed. Understanding the role of these molecular mechanisms during the ageing process will contribute towards the development of targeted therapies that will improve protein metabolism and reduce sarcopenia.

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Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone

Cited by 41 publications

References 68 publications

Sarcopenia in Chronic Kidney Disease: Factors, Mechanisms, and Therapeutic Interventions

Sarcopenia in Chronic Kidney Disease: Factors, Mechanisms, and Therapeutic Interventions

Detection of black market follistatin 344

Sarcopenia: Tilting the Balance of Protein Homeostasis

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