Myostatin expression in the adult rat central nervous system

Hayashi, Yutaro; Mikawa, Sumiko; Ogawa, Chikara; Masumoto, Kazuma; Katou, Fuminori; Sato, Kohji

doi:10.1016/j.jchemneu.2018.10.001

Cited by 10 publications

(7 citation statements)

References 20 publications

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“…Nevertheless, immunohistochemical analysis of GDF11 in the adult rat CNS indicated that GDF11 is widely expressed throughout the adult brain, including the olfactory bulb, cortex, nucleus accumbens, caudate putamen, hippocampus, thalamus, hypothalamus, midbrain, cerebellum, brainstem, and spinal cord, with observed expression in neurons, astrocytes, and ependymal cells (Hayashi et al 2018a). Similar expression patterns were observed for MSTN/GDF8 in the adult rat brain also using antibody-based detection, raising questions of functional redundancy and/or detection cross-reactivity (Hayashi et al 2018b).…”

Section: Gdf11 Expression In the Cnsmentioning

confidence: 61%

The influence of GDF11 on brain fate and function

Schafer

LeBrasseur

2019

GeroScience

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Growth differentiation factor 11 (GDF11) is a transforming growth factor β (TGFβ) protein that regulates aspects of central nervous system (CNS) formation and health throughout the lifespan. During development, GDF11 influences CNS patterning and the genesis, differentiation, maturation, and activity of new cells, which may be primarily dependent on local production and action. In the aged brain, exogenous, peripherally delivered GDF11 may enhance neurogenesis and angiogenesis, as well as improve neuropathological outcomes. This is in contrast to a predominantly negative influence on neurogenesis in the developing CNS. Seemingly antithetical effects may correspond to the cell types and mechanisms activated by local versus circulating concentrations of GDF11. Yet undefined, distinct mechanisms of action in young and aged brains may also play a role, which could include differential receptor and binding partner interactions. Exogenously increasing circulating GDF11 concentrations may be a viable approach for improving deleterious aspects of brain aging and neuropathology. Caution is warranted, however, since GDF11 appears to negatively influence muscle health and body composition. Nevertheless, an expanding understanding of GDF11 biology suggests that it is an important regulator of CNS formation and fate, and its manipulation may improve aspects of brain health in older organisms.

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Section: Gdf11 Expression In the Cnsmentioning

confidence: 61%

The influence of GDF11 on brain fate and function

Schafer

LeBrasseur

2019

GeroScience

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“…Since we reported the reduced endocranial phenotype in 2014, several studies have reported the abundant expression of myostatin‐like proteins throughout the brain, including glia as well as neurons (e.g. Augustin et al, 2017; Hayashi et al, 2018; Schafer et al, 2019). This suggests myostatin is an important factor for neuronal growth and maintenance.…”

Section: Discussionmentioning

confidence: 82%

Ontogenetic and in silico models of spatial‐packing in the hypermuscular mouse skull

2021

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Anatomical structures physically interact to varying degrees throughout ontogeny, adulthood, and evolution. During ontogeny, genetically mediated changes in one structure can simultaneously affect important epigenetic changes in several surrounding structures. Moreover, interactions that reliably generate the same or similar phenotypes over successive ontogenies can shield from selection mutations in genes that would have otherwise defined those traits (see Green et al., 2017;Lahti et al., 2009;Zheng et al., 2019). These mutations can then accumulate, leading to punctuated phenotypic diversification as conditions prevail that destabilise the protective network of interactions and expose the gene variants to selection (Gould, 2002;Laland et al., 2015). Interactions also allow for phenotypic adjustments during life, which can accommodate behavioural changes of, for example, dietary niche or physical activity (e.g. Anderson et al., 2014). This capability extends into adulthood and can help genetically similar individuals and populations to tolerate and thrive under different environmental conditions (see Murren et al, 2015). The premise that structural interactions help define and maintain morphological outcomes has a long history and has taken many forms

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“…Modulation of activin and follistatin levels has led to anxiety-related behavior with altered locomotor activity in transgenic mice. 35 Since myostatin is expressed in the CNS, 36 we evaluated the impact of apitegromab treatment on the FOB, locomotor activity, and developmental neurohistopathology in juvenile rats. There were no apitegromab-related adverse observations on any of these endpoints, confirming that in juvenile rodents, the specific inhibition of latent myostatin by apitegromab does not result in any undesirable impact on the CNS.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease

et al. 2021

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Myostatin is a negative regulator of skeletal muscle and has become a therapeutic target for muscle atrophying disorders. Although previous inhibitors of myostatin offered promising preclinical data, these therapies demonstrated a lack of specificity toward myostatin signaling and have shown limited success in the clinic. Apitegromab is a fully human, monoclonal antibody that binds to human promyostatin and latent myostatin with a high degree of specificity, without binding mature myostatin and other closely related growth factors. To support the clinical development of apitegromab, we present data from a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies confirmed the ability of apitegromab to inhibit the activation of promyostatin. Toxicology studies in monkeys for 4 weeks and in adult rats for up to 26 weeks showed that weekly intravenous administration of apitegromab achieved sustained serum exposure and target engagement and was well-tolerated, with no treatment-related adverse findings at the highest doses tested of up to 100 mg/kg and 300 mg/kg in monkeys and rats, respectively. Additionally, results from an 8-week juvenile rat study showed no adverse effects on any endpoint, including neurodevelopmental, motor, and reproductive outcomes at 300 mg/kg administered weekly IV. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that apitegromab is a selective inhibitor of proforms of myostatin that does not exhibit toxicities observed with other myostatin pathway inhibitors. These data support the conduct of ongoing clinical studies of apitegromab in adult and pediatric patients with spinal muscular atrophy (SMA).

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Myostatin expression in the adult rat central nervous system

Cited by 10 publications

References 20 publications

The influence of GDF11 on brain fate and function

The influence of GDF11 on brain fate and function

Ontogenetic and in silico models of spatial‐packing in the hypermuscular mouse skull

Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease

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