The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle

Rybalka, Emma; Timpani, Cara A; Debruin, Danielle A; Bagaric, Ryan M; Campelj, Dean G; Hayes, Alan

doi:10.3390/cells9122657

Cited by 45 publications

(29 citation statements)

References 135 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another pathway is myostatin inhibition using compounds such as follistatin, ACE-031, domagrozumab, and the GDF11 propeptide that inhibit or antagonize the effect of myostatin [ 52 , 53 , 54 , 55 , 56 , 57 ]. However, the results from animal models and patients with DMD have raised some concerns related to other biological functions of myostatin that affect the metabolism and oxidative capacity of muscle fibers [ 52 , 58 ]. Second, genotyping of patients with DMD for LTBP4 and SPP1 could be considered, especially in the Caucasian population.…”

Section: Discussionmentioning

confidence: 99%

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

et al. 2021

View full text Add to dashboard Cite

The transforming growth factor beta (TGFβ) pathway could modulate the Duchenne muscular dystrophy (DMD) phenotype. This meta-analysis aims to estimate the association of genetic variants involved in the TGFβ pathway, including the latent transforming growth factor beta binding protein 4 (LTBP4) and secreted phosphoprotein 1 (SPP1) genes, among others, with age of loss of ambulation (LoA) and cardiac function in patients with DMD. Meta-analyses were conducted for the hazard ratio (HR) of LoA for each genetic variant. A subgroup analysis was performed in patients treated exclusively with glucocorticoids. Eight studies were included in the systematic review and four in the meta-analyses. The systematic review suggests a protective effect of LTBP4 haplotype IAAM (recessive model) for LoA. It is also suggested that the SPP1 rs28357094 genotype G (dominant model) is associated with early LoA in glucocorticoids-treated patients. The meta-analysis of the LTBP4 haplotype IAAM showed a protective association with LoA, with an HR = 0.78 (95% CI: 0.67–0.90). No association with LoA was observed for the SPP1 rs28357094. The LTBP4 haplotype IAAM is associated with a later LoA, especially in the Caucasian population, while the SPP1 rs28357094 genotype G could be associated with a poor response to glucocorticoids. Future research is suggested for SPP1 rs11730582, LTBP4 rs710160, and THBS1 rs2725797.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Additional clinical data on patients with muscle atrophy-linked neuromuscular disorders reveal that patients with advanced muscle wasting and atrophy have significant decreases in circulating myostatin levels and myostatin expression in muscle biopsies ( Burch et al, 2017 ; Mariot et al, 2017 ) in contrast to other studies ( Brandt et al, 2012 ). Myostatin antagonists, employed in clinical trials in DMD, for example, may thus be targeting an already down-regulated ligand, resulting in less significant patient outcomes ( Mariot et al, 2017 ; Rybalka et al, 2020 ). A recent 2020 review by Rybalka and colleagues highlights this and other biological and therapeutic reasons for the lack of success with using myostatin inhibitors in human DMD ( Rybalka et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Myostatin antagonists, employed in clinical trials in DMD, for example, may thus be targeting an already down-regulated ligand, resulting in less significant patient outcomes ( Mariot et al, 2017 ; Rybalka et al, 2020 ). A recent 2020 review by Rybalka and colleagues highlights this and other biological and therapeutic reasons for the lack of success with using myostatin inhibitors in human DMD ( Rybalka et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…In its active form, myostatin binds and signals primarily through activin receptor type II B (ActRIIB), a serine/threonine kinase, which dimerizes with activin receptor-like kinase 4 (ALK4) and effects changes in the Smad signaling pathway ( Figure 1B ). Myostatin is also capable of effecting a non-canonical signaling cascade involving the cellular energy-sensing enzyme AMP-activated kinase (AMPK) and a regulatory protein kinase transforming growth factor-β-activated kinase 1 (TAK1; Biesemann et al, 2014 ; Rybalka et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

Omosule

Phillips

2021

Front. Genet.

View full text Add to dashboard Cite

Current research findings in humans and other mammalian and non-mammalian species support the potent regulatory role of myostatin in the morphology and function of muscle as well as cellular differentiation and metabolism, with real-life implications in agricultural meat production and human disease. Myostatin null mice (mstn−/−) exhibit skeletal muscle fiber hyperplasia and hypertrophy whereas myostatin deficiency in larger mammals like sheep and pigs engender muscle fiber hyperplasia. Myostatin’s impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease. In this review, we explore myostatin’s role in skeletal integrity and bone cell biology either due to direct biochemical signaling or indirect mechanisms of mechanotransduction. In vitro, myostatin inhibits osteoblast differentiation and stimulates osteoclast activity in a dose-dependent manner. Mice deficient in myostatin also have decreased osteoclast numbers, increased cortical thickness, cortical tissue mineral density in the tibia, and increased vertebral bone mineral density. Further, we explore the implications of these biochemical and biomechanical influences of myostatin signaling in the pathophysiology of human disorders that involve musculoskeletal degeneration. The pharmacological inhibition of myostatin directly or via decoy receptors has revealed improvements in muscle and bone properties in mouse models of osteogenesis imperfecta, osteoporosis, osteoarthritis, Duchenne muscular dystrophy, and diabetes. However, recent disappointing clinical trial outcomes of induced myostatin inhibition in diseases with significant neuromuscular wasting and atrophy reiterate complexity and further need for exploration of the translational application of myostatin inhibition in humans.

show abstract

“…Conversely, in those very same studies showing elevated activin A, circulating myostatin was found decreased [147,149], similar to myostatin gene expression in gastric cancer patients with minimal or no weight loss [152,153]. Interestingly, circulating myostatin is substantially lower in humans than in mice [154], perhaps contributing to the poor translation of blocking myostatin alone [19]. More studies are needed to fully understand the role of activin A in muscle atrophy, also keeping in mind that low muscle size, as calculated from computed tomography (CT) scans, was not found to correlate with activin A levels [148].…”

Section: Levels Of Acvr2 Ligands In Cancer Cachexia and In Cancer Treatmentmentioning

confidence: 93%

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

Hulmi

Nissinen

Penna

et al. 2021

Cells

View full text Add to dashboard Cite

Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.

show abstract

The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle

Cited by 45 publications

References 135 publications

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

Contact Info

Product

Resources

About