Systemic administration of monovalent follistatin-like 3-Fc-fusion protein increases muscle mass in mice

Ozawa, Takayuki; Morikawa, Masato; Morishita, Yasuyuki; Ogikubo, Kazuki; Itoh, Fumiko; Koinuma, Daizo; Nygren, Per‐Åke; Miyazono, Kohei

doi:10.1016/j.isci.2021.102488

Cited by 12 publications

(26 citation statements)

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“…For introducing the knobs-into-holes mutation T366W or T366S/L368A/Y407V ( Atwell et al., 1997 ; Ridgway et al., 1996 ), site-directed mutagenesis is performed using PCR with specific primers ( Figure 1 ). Complete amino acid sequences of the mono-FSTL3-Fc heterodimer are available in Ozawa et al. (2021) .…”

Section: Step-by-step Methods Detailsmentioning

confidence: 99%

“…We further outline the steps for validation of mono-FSTL3-Fc increasing systemic muscle mass in mice after intraperitoneal administration. For complete details on the use and execution of this protocol, please refer to Ozawa et al. (2021) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Ozawa et al. (2021) .…”

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confidence: 99%

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Preparation of monovalent follistatin-like 3-Fc-fusion protein and evaluation of its effects on muscle mass in mice

2021

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Summary Follistatin-like 3 (FSTL3) is an endogenous antagonist against transforming growth factor-β family ligands. Monovalent FSTL3-Fc fusion protein (mono-FSTL3-Fc) generated with knobs-into-holes technology overcomes limitations of current anti-myostatin therapies. We have developed a facile protocol for affinity purification of the Fc-fused protein from the supernatant of HEK293T cells stably expressing the protein. This protocol is advantageous by only requiring readily accessible equipment. We further outline the steps for validation of mono-FSTL3-Fc increasing systemic muscle mass in mice after intraperitoneal administration. For complete details on the use and execution of this protocol, please refer to Ozawa et al. (2021) .

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Section: Step-by-step Methods Detailsmentioning

confidence: 99%

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confidence: 99%

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Preparation of monovalent follistatin-like 3-Fc-fusion protein and evaluation of its effects on muscle mass in mice

2021

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“…In a multicenter, phase 2 study of patients aged ≥75 years with a history of fall, administration of humanized myostatin antibody LY2495655 (LY) increased lean muscle mass and improved several performance-based measures [ 158 ]. However, targeting a broad spectrum of TGF-β family members can induce adverse effects, such as telangiectasia and epistaxis [ 161 , 162 ]. In addition, myostatin is expressed in cardiac tissue, and sustained myostatin inhibition might cause cardiomyopathy [ 163 ].…”

Section: Osteosarcopenia In Chronic Liver Diseasementioning

confidence: 99%

“…A recent in vivo study focused on another endogenous antagonist, follistatin-like 3 (FSTL3), which has a more restricted binding profile for TGF-β family ligands. The administration of FSTL3 Fc-fusion protein promoted muscle fiber hypertrophy and increased muscle mass [ 162 ]. Accordingly, molecular target treatments have either been developed or are under investigation for osteoporosis and sarcopenia.…”

Section: Osteosarcopenia In Chronic Liver Diseasementioning

confidence: 99%

Influencing Factors and Molecular Pathogenesis of Sarcopenia and Osteosarcopenia in Chronic Liver Disease

Saeki

Tsubota

2021

Life

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The liver plays a pivotal role in nutrient/energy metabolism and storage, anabolic hormone regulation, ammonia detoxification, and cytokine production. Impaired liver function can cause malnutrition, hyperammonemia, and chronic inflammation, leading to an imbalance between muscle protein synthesis and proteolysis. Patients with chronic liver disease (CLD) have a high prevalence of sarcopenia, characterized by progressive loss of muscle mass and function, affecting health-related quality of life and prognosis. Recent reports have revealed that osteosarcopenia, defined as the concomitant occurrence of sarcopenia and osteoporosis, is also highly prevalent in patients with CLD. Since the differentiation and growth of muscles and bones are closely interrelated through mechanical and biochemical communication, sarcopenia and osteoporosis often progress concurrently and affect each other. Osteosarcopenia further exacerbates unfavorable health outcomes, such as vertebral fracture and frailty. Therefore, a comprehensive assessment of sarcopenia, osteoporosis, and osteosarcopenia, and an understanding of the pathogenic mechanisms involving the liver, bones, and muscles, are important for prevention and treatment. This review summarizes the molecular mechanisms of sarcopenia and osteosarcopenia elucidated to data in hopes of promoting advances in treating these musculoskeletal disorders in patients with CLD.

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Nanoparticle‐Based Follistatin Messenger RNA Therapy for Reprogramming Metastatic Ovarian Cancer and Ameliorating Cancer‐Associated Cachexia

Korzun

Moses

Kim

et al. 2022

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This study presents the first messenger RNA (mRNA) therapy for metastatic ovarian cancer and cachexia‐induced muscle wasting based on lipid nanoparticles that deliver follistatin (FST) mRNA predominantly to cancer clusters following intraperitoneal administration. The secreted FST protein, endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with aggressive ovarian cancer and associated cachexia. By altering the cancer cell phenotype, mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors, and preserves muscle mass in cancer‐bearing mice by inhibiting negative regulators of muscle mass. Finally, mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and counteracting muscle atrophy induced by chemotherapy and cancer‐associated cachexia. The treated mice develop few nonadherent tumors that are easily resected from the peritoneum. Clinically, this nanomedicine‐based mRNA therapy can facilitate complete cytoreduction, target resistance, improve resilience during aggressive chemotherapy, and improve survival in advanced ovarian cancer.

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Systemic administration of monovalent follistatin-like 3-Fc-fusion protein increases muscle mass in mice

Cited by 12 publications

References 63 publications

Preparation of monovalent follistatin-like 3-Fc-fusion protein and evaluation of its effects on muscle mass in mice

Preparation of monovalent follistatin-like 3-Fc-fusion protein and evaluation of its effects on muscle mass in mice

Influencing Factors and Molecular Pathogenesis of Sarcopenia and Osteosarcopenia in Chronic Liver Disease

Nanoparticle‐Based Follistatin Messenger RNA Therapy for Reprogramming Metastatic Ovarian Cancer and Ameliorating Cancer‐Associated Cachexia

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