Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha

AbstractThyroid hormone signaling plays an essential role in muscle development and function, in the maintenance of muscle mass, and in regeneration after injury, via activation of thyroid nuclear receptor alpha (THRA). A mouse model of resistance to thyroid hormone carrying a frame-shift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury. The expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA-PV mice and it is known to negatively regulate myogenesis. Here, we report that in murine myoblasts COUP-TFII interacts with THRA and modulates THRA binding to thyroid response elements (TREs). Silencing of COUP-TFII expression restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts. Moreover, COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice.

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Persistent COUP-TFII Expression Underlies the Myopathy and Impaired Muscle Regeneration Observed in Resistance to Thyroid Hormone-Alpha

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1658 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A814-A814

Author(s):

Paola Aguiari ◽

Yan-Yun Liu ◽

Astgik Petrosyan ◽

Sheue-Yann Cheng ◽

Gregory A Brent ◽

...

Keyword(s):

Skeletal Muscle ◽

Thyroid Hormone ◽

Muscle Regeneration ◽

Myogenic Differentiation ◽

Skeletal Muscle Regeneration ◽

Hormone Signaling ◽

Muscle Loss ◽

Resistance To Thyroid Hormone ◽

Skeletal Muscle Loss

Abstract Myopathic changes, including muscular dystrophy and weakness, are commonly described in hypothyroid and hyperthyroid patients. Thyroid hormone signaling, via activation of thyroid nuclear receptor alpha (THRA), plays an essential role in maintaining muscle mass, function, and regeneration. A mouse model of resistance to thyroid hormone carrying a frameshift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury(1,2). We previously demonstrated that the expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA- PV mice. COUP-TFII is known to regulate myogenesis negatively and has a role in Duchenne-like Muscular Dystrophies(3). COUP-TFII physically and functionally interacts with THRA in primary myoblasts isolated from WT and THRA-PV mice, as demonstrated via co-immunoprecipitation and chromatin-immunoprecipitation. We observed that satellite cells from THRA-PV mice display impaired myoblast proliferation and in vitro myogenic differentiation compared to WT cells. However, the silencing of COUP-TFII expression using siRNA probes restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts, with a higher proliferation of myoblasts and a higher number of fully differentiated myotubes after 5 days of myogenic induction. Moreover, RNAseq analysis on myoblasts from THRA-PV mice after COUP-TFII knockdown shows that COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during murine post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice. These studies can help increase our knowledge of the mechanisms involved in thyroid hormone signaling during skeletal muscle regeneration, ultimately increasing the possibility of designing more specific treatments for patients with thyroid hormone-induced myopathies. References: 1. Milanesi, A., et al., Endocrinology 2016; 2. Kaneshige, M. et al., Proc Natl Acad Sci U S 2001; 3. Lee HJ, et al, Sci Rep. 2017.

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OR01-03 Thyroid Receptor Alpha Interacts with COUP-TFII in the Regulation of Postnatal Skeletal Muscle Regeneration

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1618 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Paola Aguiari ◽

Astgik Petrosyan ◽

Yan-Yun Liu ◽

Sheue-Yann Cheng ◽

Laura Perin ◽

...

Keyword(s):

Skeletal Muscle ◽

Thyroid Hormone ◽

Satellite Cells ◽

Muscle Regeneration ◽

Myogenic Differentiation ◽

Orphan Receptor ◽

Skeletal Muscle Regeneration ◽

Myoblast Differentiation ◽

Hormone Signaling

Abstract Myopathic changes, including muscular dystrophy and weakness, are commonly described in hypothyroid and hyperthyroid patients. Thyroid hormone signaling, via activation of thyroid nuclear receptors (TRs), plays an essential role in the maintenance of muscle mass, function, and regeneration. TRs are ligand-inducible transcription factors expressed in almost all tissues, including skeletal muscle. In a mouse model of Resistance to Thyroid Hormone carrying a frame-shift mutation in the TRα gene (TRα1PV)1,2 we observed skeletal muscle loss with aging and impaired skeletal muscle regeneration after injury. We recently described that TRα interacts with the nuclear orphan receptor Chicken Ovalbumin Upstream Promoter-factor II (COUP-TFII, or NR2F2), which is known to regulate myogenesis negatively and has a role in Duchenne-like Muscular Dystrophies3. We showed that COUP-TFII expression declines with age in WT mice, while the skeletal muscle of TRα1PV mice shows a sustained significantly higher expression of COUP-TFII. Our findings suggest that the TRα/COUP-TFII interaction might mediate the impaired skeletal muscle phenotype observed in TRα1PV mice. To better characterize this interaction, we isolated SC from 10 months old WT and TRα1PV mice and cultured them in vitro using novel methods established within our lab. Using siRNA probes, we next silenced COUP-TFII and characterized the cells via RNA-seq analysis. In vitro, we assessed myoblast differentiation and proliferation using differentiation assays and EdU incorporation. We observed that satellite cells from TRα1PV mice display impaired myoblast proliferation and in vitro myogenic differentiation compared to WT SCs. However, when COUP-TFII was silenced, the myogenic potential of TRα1PV satellite cells was restored, with a higher proliferation of myoblasts and a higher number of fully differentiated myotubes after 4 days of myogenic induction. RNAseq analysis on satellite cells from TRα1PV mice after COUP-TFII knockdown showed upregulation of genes involved in the myogenic pathway, such as Myod1 and Pax7, and of genes in the thyroid hormone signaling, such as Dio2. Ingenuity Pathway Analysis further showed activation of pathways regarding cell growth, differentiation, matrix remodeling along with muscle function, muscle contractility, and muscle contraction. These in vitro results suggest that by silencing COUP-TFII we promote the myogenic pathway and may further rescue the impaired phenotype of TRα1PV mice. These studies can help increase our knowledge of the mechanisms involved in thyroid hormone signaling in skeletal muscle regeneration, which will ultimately increase the possibility of designing more specific treatments for patients with thyroid hormone-induced myopathies. References: 1Milanesi, A., et al, Endocrinology 2016; 2Kaneshige, M. et al, Proc Natl Acad Sci U S 2001; 3Lee HJ, et al, Sci Rep. 2017.

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SAT-560 Role of COUP-TFII and Thyroid Hormone Receptor α in Skeletal Muscle Loss

Journal of the Endocrine Society ◽

10.1210/js.2019-sat-560 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Paola Aguiari ◽

Yan-Yun Liu ◽

Sheue-Yann Cheng ◽

Laura Perin ◽

Gregory Brent ◽

...

Keyword(s):

Skeletal Muscle ◽

Thyroid Hormone ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Muscle Loss ◽

Skeletal Muscle Loss ◽

Thyroid Hormone Receptor Α

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Pannexin 1 Regulates Skeletal Muscle Regeneration by Promoting Bleb-Based Myoblast Migration and Fusion Through a Novel Lipid Based Signaling Mechanism

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.736813 ◽

2021 ◽

Vol 9 ◽

Author(s):

Katia Suarez-Berumen ◽

Henry Collins-Hooper ◽

Anastasia Gromova ◽

Robyn Meech ◽

Alessandra Sacco ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Muscle Development ◽

Myogenic Differentiation ◽

Skeletal Muscle Regeneration ◽

Stem Cell Population ◽

Amoeboid Movement ◽

Paracrine Signaling ◽

Signaling Mechanism ◽

Adult Skeletal Muscle

Adult skeletal muscle has robust regenerative capabilities due to the presence of a resident stem cell population called satellite cells. Muscle injury leads to these normally quiescent cells becoming molecularly and metabolically activated and embarking on a program of proliferation, migration, differentiation, and fusion culminating in the repair of damaged tissue. These processes are highly coordinated by paracrine signaling events that drive cytoskeletal rearrangement and cell-cell communication. Pannexins are a family of transmembrane channel proteins that mediate paracrine signaling by ATP release. It is known that Pannexin1 (Panx1) is expressed in skeletal muscle, however, the role of Panx1 during skeletal muscle development and regeneration remains poorly understood. Here we show that Panx1 is expressed on the surface of myoblasts and its expression is rapidly increased upon induction of differentiation and that Panx1–/– mice exhibit impaired muscle regeneration after injury. Panx1–/– myoblasts activate the myogenic differentiation program normally, but display marked deficits in migration and fusion. Mechanistically, we show that Panx1 activates P2 class purinergic receptors, which in turn mediate a lipid signaling cascade in myoblasts. This signaling induces bleb-driven amoeboid movement that in turn supports myoblast migration and fusion. Finally, we show that Panx1 is involved in the regulation of cell-matrix interaction through the induction of ADAMTS (Disintegrin-like and Metalloprotease domain with Thrombospondin-type 5) proteins that help remodel the extracellular matrix. These studies reveal a novel role for lipid-based signaling pathways activated by Panx1 in the coordination of myoblast activities essential for skeletal muscle regeneration.

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EphA7 promotes myogenic differentiation via cell-cell contact

eLife ◽

10.7554/elife.53689 ◽

2020 ◽

Vol 9 ◽

Author(s):

Laura L Arnold ◽

Alessandra Cecchini ◽

Danny A Stark ◽

Jacqueline Ihnat ◽

Rebecca N Craigg ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Muscle Development ◽

Myogenic Differentiation ◽

Cell Contact ◽

Postnatal Life ◽

Differentiation Markers ◽

Hindlimb Muscles

The conversion of proliferating skeletal muscle precursors (myoblasts) to terminally-differentiated myocytes is a critical step in skeletal muscle development and repair. We show that EphA7, a juxtacrine signaling receptor, is expressed on myocytes during embryonic and fetal myogenesis and on nascent myofibers during muscle regeneration in vivo. In EphA7-/- mice, hindlimb muscles possess fewer myofibers at birth, and those myofibers are reduced in size and have fewer myonuclei and reduced overall numbers of precursor cells throughout postnatal life. Adult EphA7-/- mice have reduced numbers of satellite cells and exhibit delayed and protracted muscle regeneration, and satellite cell-derived myogenic cells from EphA7-/- mice are delayed in their expression of differentiation markers in vitro. Exogenous EphA7 extracellular domain will rescue the null phenotype in vitro, and will also enhance commitment to differentiation in WT cells. We propose a model in which EphA7 expression on differentiated myocytes promotes commitment of adjacent myoblasts to terminal differentiation.

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Time course of skeletal muscle loss and oxidative stress in rats with walker 256 solid tumor

Muscle & Nerve ◽

10.1002/mus.21798 ◽

2010 ◽

Vol 42 (6) ◽

pp. 950-958 ◽

Cited By ~ 38

Author(s):

Flávia A. Guarnier ◽

Alessandra L. Cecchini ◽

Andréia A. Suzukawa ◽

Ana Leticia G.C. Maragno ◽

Andréa N.C. Simão ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Solid Tumor ◽

Time Course ◽

Muscle Loss ◽

Skeletal Muscle Loss ◽

Walker 256 ◽

And Oxidative Stress

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The LIM domain protein nTRIP6 modulates the dynamics of myogenic differentiation

Scientific Reports ◽

10.1038/s41598-021-92331-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tannaz Norizadeh Abbariki ◽

Zita Gonda ◽

Denise Kemler ◽

Pavel Urbanek ◽

Tabea Wagner ◽

...

Keyword(s):

Skeletal Muscle ◽

Satellite Cells ◽

Muscle Regeneration ◽

Myogenic Differentiation ◽

Skeletal Muscle Regeneration ◽

Temporal Control ◽

Lim Domain ◽

Lim Domain Protein ◽

Domain Protein

AbstractThe process of myogenesis which operates during skeletal muscle regeneration involves the activation of muscle stem cells, the so-called satellite cells. These then give rise to proliferating progenitors, the myoblasts which subsequently exit the cell cycle and differentiate into committed precursors, the myocytes. Ultimately, the fusion of myocytes leads to myofiber formation. Here we reveal a role for the transcriptional co-regulator nTRIP6, the nuclear isoform of the LIM-domain protein TRIP6, in the temporal control of myogenesis. In an in vitro model of myogenesis, the expression of nTRIP6 is transiently up-regulated at the transition between proliferation and differentiation, whereas that of the cytosolic isoform TRIP6 is not altered. Selectively blocking nTRIP6 function results in accelerated early differentiation followed by deregulated late differentiation and fusion. Thus, the transient increase in nTRIP6 expression appears to prevent premature differentiation. Accordingly, knocking out the Trip6 gene in satellite cells leads to deregulated skeletal muscle regeneration dynamics in the mouse. Thus, dynamic changes in nTRIP6 expression contributes to the temporal control of myogenesis.

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