Fiber Type-Specific Expression of Low-Density Lipoprotein Receptor-Related Protein 6 in Human Skeletal Muscles

Takeda, Ikuko; Takahashi, Tetsuya; Ochi, Kazuhide; Kurashige, Takashi; Shinozaki, Yukari; Nakamori, Masahiro; Arihiro, Koji; Makino, Hírofumi; Matsumoto, Masayasu

doi:10.1159/000357238

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…Activation of Wnt‐YAP signaling following increased (P)RR is tightly involved in the induction of skeletal muscle atrophy, but it remains unclear how (P)RR activates Wnt‐YAP signaling selectively in fast muscle. The Wnt receptor LRP6, a binding partner of (P)RR, has been reported to be predominantly expressed in fast muscle (Takeda et al, ). The expression pattern of LRP6 may contribute to fast muscle‐specific activation of the Wnt pathway in (P)RR‐Tg mice.…”

Section: Discussionmentioning

confidence: 99%

(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis

et al. 2019

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To extend life expectancy and ensure healthy aging, it is crucial to prevent and minimize age‐induced skeletal muscle atrophy, also known as sarcopenia. However, the disease's molecular mechanism remains unclear. The age‐related Wnt/β‐catenin signaling pathway has been recently shown to be activated by the (pro)renin receptor ((P)RR). We report here that (P)RR expression was increased in the atrophied skeletal muscles of aged mice and humans. Therefore, we developed a gain‐of‐function model of age‐related sarcopenia via transgenic expression of (P)RR under control of the CAG promoter. Consistent with our hypothesis, (P)RR‐Tg mice died early and exhibited muscle atrophy with histological features of sarcopenia. Moreover, Wnt/β‐catenin signaling was activated and the regenerative capacity of muscle progenitor cells after cardiotoxin injury was impaired due to cell fusion failure in (P)RR‐Tg mice. In vitro forced expression of (P)RR protein in C2C12 myoblast cells suppressed myotube formation by activating Wnt/β‐catenin signaling. Administration of Dickkopf‐related protein 1, an inhibitor of Wnt/β‐catenin signaling, and anti‐(P)RR neutralizing antibody, which inhibits binding of (P)RR to the Wnt receptor, significantly improved sarcopenia in (P)RR‐Tg mice. Furthermore, the use of anti‐(P)RR neutralizing antibodies significantly improved the regenerative ability of skeletal muscle in aged mice. Finally, we show that Yes‐associated protein (YAP) signaling, which is coordinately regulated by Wnt/β‐catenin, contributed to the development of (P)RR‐induced sarcopenia. The present study demonstrates the use of (P)RR‐Tg mice as a novel sarcopenia model, and shows that (P)RR‐Wnt‐YAP signaling plays a pivotal role in the pathogenesis of this disease.

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Section: Discussionmentioning

confidence: 99%

(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis

et al. 2019

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“…In this regard, the Wnt/β-catenin signaling pathway is anabolic in skeletal muscle [ 32 ] and sclerostin co-incubation has been shown to abolish Wnt3a-mediated C2C12 differentiation in culture, demonstrating that sclerostin antagonizes Wnt-signaling in an isolated murine muscle cell line [ 13 ]. However, LRP6 expression is fiber-type specific, with normal and atrophic human skeletal muscle expressing LRP6 only in type II fibers and C2C12 cells expressing LRP6 only in the presence of fast myosin [ 12 ], explaining the relatively low LRP6 mRNA expression that we observed in the soleus, a muscle comprised predominantly of type I fibers. In comparison, Tran et al reported >50% of cultured myoblasts from murine muscle were LRP5 positive, although, satellite cells for this experiment were isolated from the tibialis anterior [ 32 ], which is composed of predominantly type II fibers.…”

Section: Discussionmentioning

confidence: 99%

“…Sclerostin influences SCI-induced bone loss, as evidenced by (1) increased sclerostin mRNA expression in bone acutely after SCI [ 7 ], (2) mice with sclerostin gene deletion that do not exhibit bone loss after spinal cord transection [ 9 ], and (3) the ability pharmacologic sclerostin-inhibition to completely prevent cancellous bone loss in rats following SCI [ 2 , 10 ]. Others have suggested that sclerostin may also influence skeletal muscle [ 5 ], a supposition that is strengthened by the understanding that sclerostin is present in the circulation [ 8 ], that LRP5/LRP6 are expressed in human muscle [ 11 , 12 ], and that the Wnt/β-catenin signaling pathway is anabolic in muscle [ 3 ]. Interestingly, Huang et al recently reported that Wnt3a, an osteocyte-derived Wnt-signaling agonist, promoted C2C12 cell differentiation in vitro and that sclerostin co-incubation (100 ng/ml) prevented this effect [ 13 ], demonstrating that sclerostin negatively regulates Wnt-signaling in a mouse skeletal muscle cell line, at least when present in relatively high concentrations.…”

Section: Introductionmentioning

confidence: 99%

Effects of pharmacologic sclerostin inhibition or testosterone administration on soleus muscle atrophy in rodents after spinal cord injury

Phillips

Beggs

et al. 2018

PLoS ONE

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Sclerostin is a circulating osteocyte-derived glycoprotein that negatively regulates Wnt-signaling after binding the LRP5/LRP6 co-receptors. Pharmacologic sclerostin inhibition produces bone anabolic effects after spinal cord injury (SCI), however, the effects of sclerostin-antibody (Scl-Ab) on muscle morphology remain unknown. In comparison, androgen administration produces bone antiresorptive effects after SCI and some, but not all, studies have reported that testosterone treatment ameliorates skeletal muscle atrophy in this context. Our purposes were to determine whether Scl-Ab prevents hindlimb muscle loss after SCI and compare the effects of Scl-Ab to testosterone enanthate (TE), an agent with known myotrophic effects. Male Sprague-Dawley rats aged 5 months received: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe contusion SCI, (C) SCI+TE (7.0 mg/wk, im), or (D) SCI+Scl-Ab (25 mg/kg, twice weekly, sc). Twenty-one days post-injury, SCI animals exhibited a 31% lower soleus mass in comparison to SHAM, accompanied by >50% lower soleus muscle fiber cross-sectional area (fCSA) (p<0.01 for all fiber types). Scl-Ab did not prevent soleus atrophy, consistent with the relatively low circulating sclerostin concentrations and with the 91–99% lower LRP5/LRP6 gene expressions in soleus versus tibia (p<0.001), a tissue with known anabolic responsiveness to Scl-Ab. In comparison, TE partially prevented soleus atrophy and increased levator ani/bulbocavernosus (LABC) mass by 30–40% (p<0.001 vs all groups). The differing myotrophic responsiveness coincided with a 3-fold higher androgen receptor gene expression in LABC versus soleus (p<0.01). This study provides the first direct evidence that Scl-Ab does not prevent soleus muscle atrophy in rodents after SCI and suggests that variable myotrophic responses in rodent muscles after androgen administration are influenced by androgen receptor expression.

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“…One possibility is that sclerostin is not solely produced by osteocytes and does not just effect bone; rather, other cell types are increasingly being found to be affected by sclerostin through the systemic circulation ( Battaglino et al, 2012 ). For example, there is increasing evidence of sclerostin’s effects on skeletal muscle, which is strengthened by the fact that LRP5/LRP6 are expressed in human muscle and that the Wnt/β-catenin signaling pathway is anabolic in muscle ( Tagliaferri et al, 2015 ; Karczewska-Kupczewska et al, 2016 ; Takeda et al, 2014 ; Rudnicki and Williams, 2015 ). Interestingly, Huang and colleagues recently reported that Wnt3a, an osteocyte-derived Wnt-signaling agonist, promoted C2C12 cell differentiation in vitro and that sclerostin co-incubation (100 ng/ml) prevented this effect, demonstrating that sclerostin negatively regulates Wnt-signaling in a mouse skeletal muscle cell line, at least when present in relatively high concentrations ( Huang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Sclerostin small-molecule inhibitors promote osteogenesis by activating canonical Wnt and BMP pathways

Sangadala,

Kim,

Fernandes

et al. 2023

eLife

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Background: The clinical healing environment after a posterior spinal arthrodesis surgery is one of the most clinically challenging bone healing environments across all orthopaedic interventions due to the absence of a contained space and the need to form de novo bone. Our group has previously reported that sclerostin in expressed locally at high levels throughout a developing spinal fusion. However, the role of sclerostin in controlling bone fusion remains to be established.Methods: We computationally identified two FDA-approved drugs, as well as a single novel small molecule drug, for their ability to disrupt the interaction between sclerostin and its receptor, LRP5/6. The drugs were tested in several in vitro biochemical assays using murine MC3T3 and MSCs, assessing their ability to: (1) enhance canonical Wnt signaling, (2) promote the accumulation of the active (non-phosphorylated) form of b-catenin, and (3) enhance the intensity and signaling duration of BMP signaling. These drugs were then tested subcutaneously in rats as standalone osteoinductive agents on plain collagen sponges. Finally, the top drug candidates (called VA1 and C07) were tested in a rabbit posterolateral spine fusion model for their ability to achieve a successful fusion at 6 weeks.Results: We show that by controlling GSK3b phosphorylation, our three SMIs simultaneously enhance canonical Wnt signaling and potentiate canonical BMP signaling intensity and duration. We also demonstrate that the SMIs produce dose-dependent ectopic mineralization in vivo in rats as well as significantly increase posterolateral spine fusion rates in rabbits in vivo, both as standalone osteogenic drugs and in combination with autologous iliac crest bone graft.Conclusions: Few if any osteogenic small molecules possess the osteoinductive potency of BMP itself – that is, the ability to form de novo ectopic bone as a standalone agent. Herein, we describe two such SMIs that have this unique ability and were shown to induce de novo bone in a stringent in vivo environment. These SMIs may have the potential to be used in novel, cost-effective bone graft substitutes for either achieving spinal fusion or in the healing of critical-sized fracture defects.Funding: This work was supported by a Veteran Affairs Career Development Award (IK2-BX003845).

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Fiber Type-Specific Expression of Low-Density Lipoprotein Receptor-Related Protein 6 in Human Skeletal Muscles

Cited by 5 publications

References 24 publications

(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis

(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis

Effects of pharmacologic sclerostin inhibition or testosterone administration on soleus muscle atrophy in rodents after spinal cord injury

Sclerostin small-molecule inhibitors promote osteogenesis by activating canonical Wnt and BMP pathways

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