Myostatin in tendon maintenance and repair

Eliasson, Pernilla; Andersson, Therése; Kulas, Jana; Seemann, Petra; Aspenberg, Per

doi:10.1080/08977190903052539

Cited by 20 publications

(16 citation statements)

References 30 publications

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“…The Achilles tendon was thicker and shorter in the middle age mstn −/− mice than the wt controls (Figure 2B). Although not quantitatively measured in this work, we noticed that Achilles tendons in the mstn −/− mice were more likely to break during dissection than those in wt mice, in agreement with previous studies showing that tendon is “more brittle” in the mstn −/− mice (18, 20). Histological examination revealed marked structural disorganization around the ankle in the middle age mstn −/− mice, including misshapen irregular morphology on bone and tendon, as well as synovial thickening with infiltration of inflammatory cells (Figure 3, right panel, A–D), in contrast to the normal morphology shown in the age-matched wt mice (Figure 3, left panel, A–D).…”

Section: Resultssupporting

confidence: 92%

“…Myostatin and its receptor are detected in tendons (19). Local administration of recombinant myostatin accelerates tendon repair and maintenance in rats (20), implying a direct effect of myostatin on tendon health. This treatment increased the volume and the contraction of the callus after 8 days, but did not improve its strength (20).…”

Section: Introductionmentioning

confidence: 99%

“…Local administration of recombinant myostatin accelerates tendon repair and maintenance in rats (20), implying a direct effect of myostatin on tendon health. This treatment increased the volume and the contraction of the callus after 8 days, but did not improve its strength (20). Here, we investigated the effect of myostatin gene deletion on physical performance and ankle and wrist joint ultrastructure in young (3–6 mo) and middle age (12–15 mo) mice.…”

Section: Introductionmentioning

confidence: 99%

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Joint dysfunction and functional decline in middle age myostatin null mice

Guo

Miller

Pencina

et al. 2016

Bone

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Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn−/−), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3–6 months) to middle age (12–15 months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn−/− mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn−/− mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn−/− mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Joint dysfunction and functional decline in middle age myostatin null mice

Guo

Miller

Pencina

et al. 2016

Bone

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“…Moreover, myostatin (GDF-8), a member of the TGF-β superfamily, induced scleraxis expression in tendon fibroblasts [11,15], and mice that are deficient in myostatin expression ( MSTN −/− ) have a hypocellular tendon phenotype [11]. Scleraxis expression increased following injury to the patellar tendon [13] and FDL tendon [12], and treadmill training increases both TGF-β [26] and myostatin [27] in tendons. These previous findings along our observations are consistent with the hypothesis that scleraxis is a downstream target of TGF-β family signaling that directs the expression of genes leading to adaptive changes in tendons in response to loading.…”

Section: Discussionmentioning

confidence: 99%

Physiological loading of tendons induces scleraxis expression in epitenon fibroblasts

Mendias

Gumucio

Bakhurin

et al. 2011

Journal Orthopaedic Research

129

116

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Scleraxis is a bHLH transcription factor that plays a central role in promoting fibroblast proliferation and matrix synthesis during the embryonic development of tendons. Mice with a targeted inactivation of scleraxis (Scx−/−) fail to properly form limb tendons, but the role that scleraxis has in regulating the growth and adaptation of tendons of adult organisms is unknown. To determine if scleraxis expression changes in response to a physiological growth stimulus to tendons, we subjected adult mice that express GFP under the control of the scleraxis promoter (ScxGFP) to a six week treadmill training program designed to induce adaptive growth in Achilles tendons. Age matched sedentary ScxGFP mice were used as controls. Scleraxis expression was sparsely observed in the epitenon region of sedentary mice, but in response to treadmill training, scleraxis was robustly expressed in fibroblasts that appeared to be emerging from the epitenon and migrating into the superficial regions of tendon fascicles. Treadmill training also led to an increase in scleraxis, tenomodulin, and type I collagen gene expression as measured by qPCR. These results suggest that in addition to regulating the embryonic formation of limb tendons, scleraxis also appears to play an important role in the adaptation of adult tendons to physiological loading.

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“…The luciferase reportergene assay was performed with minor changes as previously described [38]. C2C12 cells were grown in DMEM high glucose with 10% FCS.…”

Section: Methodsmentioning

confidence: 99%

Mutations in GDF5 Reveal a Key Residue Mediating BMP Inhibition by NOGGIN

et al. 2009

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Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP–inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.

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Myostatin in tendon maintenance and repair

Cited by 20 publications

References 30 publications

Joint dysfunction and functional decline in middle age myostatin null mice

Joint dysfunction and functional decline in middle age myostatin null mice

Physiological loading of tendons induces scleraxis expression in epitenon fibroblasts

Mutations in GDF5 Reveal a Key Residue Mediating BMP Inhibition by NOGGIN

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