Myostatin Alters Muscle Composition as The Result of an ACL Injury

ACL 损伤导致肌肉生长抑制素改变肌肉成分

• 批准号: 10380581
• 负责人: Christopher Fry
• 金额: $ 43.48万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-26 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380581
• 关键词: Activins; Acute; Anabolism; Animals; Anterior Cruciate Ligament; Atrophic; Biomechanics; Biopsy; Cell Proliferation; Cells; Chronic; Clinical Trials; Collagen; Connective Tissue; Data; Degenerative polyarthritis; Development; Diffusion; Etiology; Extensor; Extracellular Matrix; Fc Receptor; Fibroblasts; Fibrosis; Follistatin; GDF8 gene; Goals; Growth; Human; Individual; Infiltration; Injury; Joints; Knee; Ligaments; Limb structure; Link; Measures; Modeling; Molecular; Morphology; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle satellite cell; Muscular Atrophy; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physical therapy; Physiological; Procedures; Public Health; Quality of life; Randomized; Reconstructive Surgical Procedures; Recovery; Rehabilitation therapy; Research; Risk; Saline; Signal Transduction; Skeletal Muscle; Testing; Time; Up-Regulation; antagonist; anterior cruciate ligament injury; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; disability; efficacy evaluation; experimental study; functional outcomes; healing; human subject; improved; ligament injury; limb injury; mouse model; muscle strength; premature; prevent; progenitor; quadriceps muscle; receptor; reconstruction; response; satellite cell; skeletal muscle weakness; stem cells; therapeutic target

Abstract Anterior cruciate ligament (ACL) reconstruction surgery results in protracted quadriceps weakness that is associated with poorer outcomes, altered biomechanics and heightened risk of subsequent injuries. Little progress has been made in improving quadriceps strength and functional outcomes in the past decade. Alterations in the cellular and morphological composition of the knee extensor muscles contribute to weakness following an ACL reconstruction. ACL reconstruction induces expression of myostatin, a negative regulator of muscle growth, locally within the quadriceps. In addition to mitigating muscle regrowth, myostatin also promotes connective tissue synthesis through activation of figrogenic cells within muscle. The objective of this proposal is to determine the time course of deleterious changes to the injured ligament and limb muscle and identify myostatin as integral in the etiology of protracted muscle weakness in individuals following an ACL tear. Aim 1 will evaluate the timeframe of myostatin induction within the injured ACL and quadriceps. Aim 2 will determine the deleterious changes within the muscle using a mouse model of ACL injury and the efficacy of follistatin and a soluble form of the myostatin receptor (activin 2B receptor) to mitigate these maladaptations. Experiments in aim 3 will determine if the competitive inhibition of myostatin is capable of rescuing ACL injury- induced skeletal muscle weakness. Finally, aim 4 will define if the acute induction of myostatin signaling following an ACL injury in human subjects predicts reductions in muscle strength, connective tissue infiltration and dysregulation of skeletal muscle progenitor cells. The identification of myostatin as a therapeutic target will establish the basis for further research to mitigate myostatin signaling after ACL and other ligamentous injuries to improve rehabilitative efforts and patient recovery.

摘要

项目成果

In vivo Measurement of Knee Extensor Muscle Function in Mice.

• DOI: 10.3791/62211
• 发表时间: 2021-03-04
• 期刊: Journal of visualized experiments : JoVE
• 作者: Brightwell CR;Graber TG;Brightwell BD;Borkowski M;Noehren B;Fry CS
• 通讯作者: Fry CS

Pharmacologic Inhibition of Myostatin With a Myostatin Antibody Improves the Skeletal Muscle and Bone Phenotype of Male Insulin-Deficient Diabetic Mice.

• DOI: 10.1002/jbm4.10833
• 发表时间: 2023-11
• 期刊: JBMR plus
• 影响因子: 3.8

T1ρ imaging as a non-invasive assessment of collagen remodelling and organization in human skeletal muscle after ligamentous injury.

• DOI: 10.1113/jp281964
• 发表时间: 2021-12
• 期刊: The Journal of physiology
• 作者: Noehren B;Hardy PA;Andersen A;Brightwell CR;Fry JL;Vandsburger MH;Thompson KL;Fry CS
• 通讯作者: Fry CS

Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction.

• DOI: 10.1172/jci.insight.170518
• 发表时间: 2023-12-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Wen, Yuan;Latham, Christine M.;Moore, Angelique N.;Thomas, Nicholas T.;Lancaster, Brooke D.;Reeves, Kelsey A.;Keeble, Alexander R.;Fry, Christopher S.;Johnson, Darren L.;Thompson, Katherine L.;Noehren, Brian;Fry, Jean L.
• 通讯作者: Fry, Jean L.

GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.

• DOI: 10.1126/sciadv.adi9134
• 发表时间: 2023-12
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Brightwell, Camille R.;Latham, Christine M.;Keeble, Alexander R.;Thomas, Nicholas T.;Owen, Allison M.;Reeves, Kelsey A.;Long, Douglas E.;Patrick, Matthew;Gonzalez-Velez, Sara;Abed, Varag;Annamalai, Ramkumar T.;Jacobs, Cale;Conley, Caitlin E.;Hawk, Gregory S.;Stone, Austin V.;Fry, Jean L.;Thompson, Katherine L.;Johnson, Darren L.;Noehren, Brian;Fry, Christopher S.
• 通讯作者: Fry, Christopher S.