GASP‐2 overexpressing mice exhibit a hypermuscular phenotype with contrasting molecular effects compared to GASP‐1 transgenics

Parenté, Alexis; Boukredine, Axel; Baraige, Fabienne; Duprat, Nathalie; Gondran-Tellier, Victor; Magnol, Laetitia; Blanquet, Véronique

doi:10.1096/fj.201901220r

Cited by 9 publications

(6 citation statements)

References 32 publications

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“…Growth differentiation factor 8 (GDF8), commonly known as myostatin, is a member of the larger transforming growth factor β (TGFβ) superfamily of signaling ligands and functions as a potent negative regulator of muscle mass (1)(2)(3)(4)(5). Genetic deletion of GDF8 or use of GDF8 inhibitors results in a drastic increase in muscle mass (1,3,(6)(7)(8)(9)(10). In contrast, overexpression of GDF8 results in muscle atrophy (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Characterization of tolloid-mediated cleavage of the GDF8 procomplex

McCoy

Goebel

Thompson

2021

Biochemical Journal

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Growth differentiation factor 8 (GDF8), a.k.a. myostatin, is a member of the larger TGFβ superfamily of signaling ligands. GDF8 has been well characterized as a negative regulator of muscle mass. After synthesis, GDF8 is held latent by a noncovalent complex between the N-terminal prodomain and the signaling ligand. Activation of latent GDF8 requires proteolytic cleavage of the prodomain at residue D99 by a member of the tolloid family of metalloproteases. While tolloid proteases cleave multiple substrates, they lack a conserved consensus sequence. Here we investigate the tolloid cleavage site of the GDF8 prodomain to determine what residues contribute to tolloid recognition and subsequent proteolysis. Using sequential alanine mutations, we identified several residues adjacent to the scissile bond, including Y94, that when mutated, abolish tolloid-mediated activation of latent GDF8. Using the astacin domain of Tll1 (Tolloid Like 1) we determined that prodomain mutants were more resistant to proteolysis. Purified latent complexes harboring the prodomain mutations, D92A and Y94A, impeded activation by tolloid but could be fully activated under acidic conditions. Finally, we show that co-expression of GDF8 WT with prodomain mutants that were tolloid resistant, suppressed GDF8 activity. Taken together our data demonstrate that residues towards the N-terminus of the scissile bond are important for tolloid-mediated activation of GDF8 and that tolloid-resistant version of the GDF8 prodomain can function dominant negative to WT GDF8.

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Section: Introductionmentioning

confidence: 99%

Characterization of tolloid-mediated cleavage of the GDF8 procomplex

McCoy

Goebel

Thompson

2021

Biochemical Journal

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“…[39] The importance of these inhibitory proteins in controlling myostatin activity is well-demonstrated through substantial muscle hypertrophy and enhanced muscle regeneration observed in mice overexpressing these proteins. Specifically, mice overexpressing FST, [12] FSTL3, [40] GASP1, [41] GASP2, [42] or LTBP3 [43] exhibit a hypermuscular phenotype, while decorin gene transfer in mice leads to an improved muscle regeneration, [44] consistent with the characteristics present in myostatin null mice. In contrast, mice lacking FST, [45] GASP1, or GASP2 [46] display reduced muscle mass and impaired muscle regeneration, effects corresponding to hyperactivity of myostatin.…”

Section: Molecular Mechanism Of Active Myostatin Signalingmentioning

confidence: 68%

Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?

Suh

Lee

2020

J Bone Metab

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Myostatin, also known as growth differentiation factor 8 (GDF8), is a transforming growth factor-β (TGF-β) family member that functions to limit skeletal muscle growth. Accordingly, loss-of-function mutations in myostatin result in a dramatic increase in muscle mass in humans and various animals, while its overexpression leads to severe muscle atrophy. Myostatin also exerts a significant effect on bone metabolism, as demonstrated by enhanced bone mineral density and bone regeneration in myostatin null mice. The identification of myostatin as a negative regulator of muscle and bone mass has sparked an enormous interest in developing myostatin inhibitors as therapeutic agents for treating a variety of clinical conditions associated with musculoskeletal disorders. As a result, various myostatin-targeting strategies involving antibodies, myostatin propeptides, soluble receptors, and endogenous antagonists have been generated, and many of them have progressed to clinical trials. Importantly, most myostatin inhibitors also repress the activities of other closely related TGF-β family members including GDF11, activins, and bone morphogenetic proteins (BMPs), increasing the potential for unwanted side effects, such as vascular side effects through inhibition of BMP 9/10 and bone weakness induced by follistatin through antagonizing several TGF-β family members. Therefore, a careful distinction between targets that may enhance the efficacy of an agent and those that may cause adverse effects is required with the improvement of the target specificity. In this review, we discuss the current understanding of the endogenous function of myostatin, and provide an overview of clinical trial outcomes from different myostatin inhibitors.

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“…While activin A and activin B are secreted in active forms, they too are neutralized by follistatin and follistatin-related proteins ( Nakamura et al, 1990 ; Tsuchida et al, 2000 ) and receptor access can be blocked by inhibin A and inhibin B ( Lewis et al, 2000 ). Many of these antagonists and soluble forms of the activin type II receptor have been shown to increase muscle mass in healthy mice and mice modeling muscle wasting conditions ( Li et al, 2007 ; Zhou et al, 2010 ; Winbanks et al, 2012 ; Parente et al, 2020 ). However, the potential side effects of molecules that target ligands with broad expression and cell tropism such as activin A/B ( Walton et al, 2012 ; Campbell et al, 2017 ) may limit their therapeutic utility.…”

Section: Discussionmentioning

confidence: 99%

TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass

et al. 2020

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Inhibition of myostatin- and activin-mediated SMAD2/3 signaling using ligand traps, such as soluble receptors, ligand-targeting propeptides and antibodies, or follistatin can increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. However, clinical translation of these extracellular approaches targeting myostatin and activin has been hindered by the challenges of achieving efficacy without potential effects in other tissues. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI), an inhibitor of transforming growth factor-β (TGF-β1)-mediated SMAD2/3 signaling, to promote growth, and counter atrophy, in skeletal muscle. In this study, we show that TMEPAI can block activin A, activin B, myostatin and GDF-11 activity in vitro . To determine the physiological significance of TMEPAI, we employed Adeno-associated viral vector (AAV) delivery of a TMEPAI expression cassette to the muscles of healthy mice, which increased mass by as much as 30%, due to hypertrophy of muscle fibers. To demonstrate that TMEPAI mediates its effects via inhibition of the SMAD2/3 pathway, tibialis anterior (TA) muscles of mice were co-injected with AAV vectors expressing activin A and TMEPAI. In this setting, TMEPAI blocked skeletal muscle wasting driven by activin-induced phosphorylation of SMAD3. In a model of cancer cachexia associated with elevated circulating activin A, delivery of AAV:TMEPAI into TA muscles of mice bearing C26 colon tumors ameliorated the muscle atrophy normally associated with cancer progression. Collectively, the findings indicate that muscle-directed TMEPAI gene delivery can inactivate the activin/myostatin-SMAD3 pathway to positively regulate muscle mass in healthy settings and models of disease.

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GASP‐2 overexpressing mice exhibit a hypermuscular phenotype with contrasting molecular effects compared to GASP‐1 transgenics

Cited by 9 publications

References 32 publications

Characterization of tolloid-mediated cleavage of the GDF8 procomplex

Characterization of tolloid-mediated cleavage of the GDF8 procomplex

Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?

TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass

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