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Article: Klotho expression is a prerequisite for proper muscle stem cell function and regeneration of skeletal muscle

von Maltzahn, Julia

Skeletal muscle, 8(1):20

2018

Abstract: BACKGROUND: Klotho is a well-known anti-aging hormone, which serves as a suppressor of aging through a variety of mechanisms. Aging of skeletal muscle is concomitant with a decrease in muscle stem cell function resulting in impaired regeneration. METHODS: ...

Institution	Leibniz-Institut für Alternsforschung
Abstract	BACKGROUND: Klotho is a well-known anti-aging hormone, which serves as a suppressor of aging through a variety of mechanisms. Aging of skeletal muscle is concomitant with a decrease in muscle stem cell function resulting in impaired regeneration. METHODS: Here we investigate the functional role of the anti-aging hormone Klotho for muscle stem cell function after cardiotoxin-induced injury of skeletal muscle using a klotho hypomorphic mouse line, which is characterized by a premature aging phenotype. Furthermore, we perform floating single myofiber cultures with their adjacent muscle stem cells to investigate the interplay between canonical Wnt signaling and Klotho function. RESULTS: We demonstrate that muscle stem cell numbers are significantly decreased in klotho hypomorphic mice. Furthermore, we show that muscle stem cell function is also severely impaired upon loss of klotho expression, in culture and during regeneration in vivo. Moreover, we demonstrate that addition of recombinant Klotho protein inhibits aberrant excessive Wnt signaling in aged muscle stem cells thereby restoring their functionality. CONCLUSIONS: The anti-aging hormone Klotho counteracts aberrant canonical Wnt signaling in muscle stem cells and might be one of the naturally occurring inhibitors of canonical Wnt signaling in skeletal muscle.
Keywords	Canonical Wnt signaling, Wnt3a ; Aging ; Klotho ; Muscle stem cell ; Myogenesis ; Skeletal muscle ; Regeneration
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article: Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration

Heuer, Heike / von Maltzahn, Julia

Stem cell reports, 10(6):1959-1974

2018

Abstract: Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and ... ...

Institution	Leibniz-Institut für Alternsforschung Leibniz-Institut für Umweltmedizinische Forschung
Abstract	Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and an abnormal TH serum profile, which is fully replicated in Mct8 knockout mice and Mct8/Oatp1c1 double-knockout (M/O DKO) mice. Analysis of tissue TH content and expression of TH-regulated genes indicate a thyrotoxic state in Mct8-deficient skeletal muscles. Both TH transporters are upregulated in activated satellite cells (SCs). In M/O DKO mice, we observed a strongly reduced number of differentiated SCs, suggesting an impaired stem cell function. Moreover, M/O DKO mice and mice lacking both transporters exclusively in SCs showed impaired skeletal muscle regeneration. Our data provide solid evidence for a unique gate-keeper function of MCT8 and OATP1C1 in SC activation, underscoring the importance of a finely tuned TH signaling during myogenesis.
Keywords	Allan-Herndon-Dudley syndrome ; SLC16A2 ; SLCO1C1 ; T3 ; T4 ; muscle stem cell ; myogenesis ; satellite cell
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article: Deficiency in mTORC1‐controlled C/EBPβ‐mRNA translation improves metabolic health in mice

von Maltzahn, Julia

EMBO reports, 16(8): 1022-1036

2015

Abstract: The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of physiological adaptations in response to changes in nutrient supply. Major downstream targets of mTORC1 signalling are the mRNA translation regulators p70 ribosomal protein S6 ...

Institution	Leibniz-Institut für Alternsforschung
Abstract	The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of physiological adaptations in response to changes in nutrient supply. Major downstream targets of mTORC1 signalling are the mRNA translation regulators p70 ribosomal protein S6 kinase 1 (S6K1p70) and the 4E‐binding proteins (4E‐BPs). However, little is known about vertebrate mRNAs that are specifically controlled by mTORC1 signalling and are engaged in regulating mTORC1‐associated physiology. Here, we show that translation of the CCAAT/enhancer binding protein beta (C/EBPβ) mRNA into the C/EBPβ‐LIP isoform is suppressed in response to mTORC1 inhibition either through pharmacological treatment or through calorie restriction. Our data indicate that the function of 4E‐BPs is required for suppression of LIP. Intriguingly, mice lacking the cis‐regulatory upstream open reading frame (uORF) in the C/EBPβ‐mRNA, which is required for mTORC1‐stimulated translation into C/EBPβ‐LIP, display an improved metabolic phenotype with features also found under calorie restriction. Thus, our data suggest that translational adjustment of C/EBPβ‐isoform expression is one of the key processes that direct metabolic adaptation in response to changes in mTORC1 activity.
Keywords	C/EBPβ ; calorie restriction ; mTORC1 ; metabolism ; translation
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article: Regulation of muscle stem cell function.

von Maltzahn, Julia

Vitamins and hormones

2021 Volume 116, Page(s) 295–311

Abstract: Regeneration of skeletal muscle is a finely tuned process which is depending on muscle stem cells, a population of stem cells in skeletal muscle which is also termed satellite cells. Muscle stem cells are a prerequisite for regeneration of skeletal ... ...

Abstract	Regeneration of skeletal muscle is a finely tuned process which is depending on muscle stem cells, a population of stem cells in skeletal muscle which is also termed satellite cells. Muscle stem cells are a prerequisite for regeneration of skeletal muscle. Of note, the muscle stem cell population is heterogeneous and subpopulations can be identified depending on gene expression or phenotypic traits. However, all muscle stem cells express the transcription factor Pax7 and their functionality is tightly controlled by intrinsic signaling pathways and extrinsic signals. The latter ones include signals form the stem cell niche as well as circulating factors such as growth factors and hormones. Among them are Wnt proteins, growth factors like IGF-1 or FGF-2 and hormones such as thyroid hormones and the anti-aging hormone Klotho. A highly orchestrated interplay between those factors and muscle stem cells is important for their full functionality and ultimately regeneration of skeletal muscle as outlined here.
MeSH term(s)	Cell Differentiation/physiology ; Muscle Development/genetics ; Muscle, Skeletal/metabolism ; Regeneration/physiology ; Satellite Cells, Skeletal Muscle/metabolism ; Stem Cells
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/bs.vh.2021.02.012
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Article: Reduced expression of C/EBPβ-LIP extends health and lifespan in mice

Müller, Christine / Tuckermann, Jan / von Maltzahn, Julia / Guryev, Victor / wang, zhao-qi / Calkhoven, Cornelis

eLife, 7:e34985

2018

Abstract: Ageing is associated with physical decline and the development of age-related diseases such as metabolic disorders and cancer. Few conditions are known that attenuate the adverse effects of ageing, including calorie restriction (CR) and reduced ... ...

Institution	Leibniz-Institut für Alternsforschung
Abstract	Ageing is associated with physical decline and the development of age-related diseases such as metabolic disorders and cancer. Few conditions are known that attenuate the adverse effects of ageing, including calorie restriction (CR) and reduced signalling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Synthesis of the metabolic transcription factor C/EBPβ-LIP is stimulated by mTORC1, which critically depends on a short upstream open reading frame (uORF) in the Cebpb-mRNA. Here, we describe that reduced C/EBPβ-LIP expression due to genetic ablation of the uORF delays the development of age-associated phenotypes in mice. Moreover, female C/EBPβΔuORF mice display an extended lifespan. Since LIP levels increase upon aging in wild type mice, our data reveal an important role for C/EBPβ in the aging process and suggest that restriction of LIP expression sustains health and fitness. Thus, therapeutic strategies targeting C/EBPβ-LIP may offer new possibilities to treat age-related diseases and to prolong healthspan.
Keywords	C/EBPβ ; Cell Biology ; Chromosomes and Gene Expression ; mTORC1 ; lifespan ; calorie restriction ; ageing ; longevity
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article: Neuron-Specific Deletion of the Nf2 Tumor Suppressor Impairs Functional Nerve Regeneration

Schulz, Alexander / Büttner, Robert / von Maltzahn, Julia / Morrison, Helen

PLOS ONE, 11(7):e0159718

2016

Abstract: In contrast to axons of the central nervous system (CNS), axons of the peripheral nervous system (PNS) show better, but still incomplete and often slow regeneration following injury. The tumor suppressor protein merlin, mutated in the hereditary tumor ... ...

Institution	Leibniz-Institut für Alternsforschung
Abstract	In contrast to axons of the central nervous system (CNS), axons of the peripheral nervous system (PNS) show better, but still incomplete and often slow regeneration following injury. The tumor suppressor protein merlin, mutated in the hereditary tumor syndrome Neurofibromatosis type 2 (NF2), has recently been shown to have RhoA regulatory functions in PNS neurons—in addition to its well-characterized, growth-inhibitory activity in Schwann cells. Here we report that the conditional knockout of merlin in PNS neurons leads to impaired functional recovery of mice following sciatic nerve crush injury, in a gene-dosage dependent manner. Gross anatomical or electrophysiological alterations of sciatic nerves could not be detected. However, correlating with attenuated RhoA activation due to merlin deletion, ultrastructural analysis of nerve samples indicated enhanced sprouting of axons with reduced caliber size and increased myelination compared to wildtype animals. We conclude that deletion of the tumor suppressor merlin in the neuronal compartment of peripheral nerves results in compromised functional regeneration after injury. This mechanism could explain the clinical observation that NF2 patients suffer from higher incidences of slowly recovering facial nerve paralysis after vestibular schwannoma surgery.
Keywords	Axons ; Muscle electrophysiology ; Neurofibromatosis type 2 ; Neurons ; Nerve fibers ; Nerve regeneration ; Nerves ; Sciatic nerves
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article ; Online: Denervation alters the secretome of myofibers and thereby affects muscle stem cell lineage progression and functionality.

Henze, Henriette / Hüttner, Sören S / Koch, Philipp / Schüler, Svenja C / Groth, Marco / von Eyss, Björn / von Maltzahn, Julia

NPJ Regenerative medicine

2024 Volume 9, Issue 1, Page(s) 10

Abstract: Skeletal muscle function crucially depends on innervation while repair of skeletal muscle relies on resident muscle stem cells (MuSCs). However, it is poorly understood how innervation affects MuSC properties and thereby regeneration of skeletal muscle. ... ...

Abstract	Skeletal muscle function crucially depends on innervation while repair of skeletal muscle relies on resident muscle stem cells (MuSCs). However, it is poorly understood how innervation affects MuSC properties and thereby regeneration of skeletal muscle. Here, we report that loss of innervation causes precocious activation of MuSCs concomitant with the expression of markers of myogenic differentiation. This aberrant activation of MuSCs after loss of innervation is accompanied by profound alterations on the mRNA and protein level. Combination of muscle injury with loss of innervation results in impaired regeneration of skeletal muscle including shifts in myogenic populations concomitant with delayed maturation of regenerating myofibers. We further demonstrate that loss of innervation leads to alterations in myofibers and their secretome, which then affect MuSC behavior. In particular, we identify an increased secretion of Osteopontin and transforming growth factor beta 1 (Tgfb1) by myofibers isolated from mice which had undergone sciatic nerve transection. The altered secretome results in the upregulation of early activating transcription factors, such as Junb, and their target genes in MuSCs. However, the combination of different secreted factors from myofibers after loss of innervation is required to cause the alterations observed in MuSCs after loss of innervation. These data demonstrate that loss of innervation first affects myofibers causing alterations in their secretome which then affect MuSCs underscoring the importance of proper innervation for MuSC functionality and regeneration of skeletal muscle.
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Journal Article
ISSN	2057-3995
ISSN (online)	2057-3995
DOI	10.1038/s41536-024-00353-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The hairpin region of WNT7A is sufficient for binding to the Frizzled7 receptor and to elicit signaling in myogenic cells.

Schmidt, Manuel / Poser, Christine / Janster, Christina / von Maltzahn, Julia

Computational and structural biotechnology journal

2022 Volume 20, Page(s) 6348–6359

Abstract: Wnt signaling is essential for embryonic development and tissue homeostasis. So far, little is known about the importance and functional relevance of the different regions in WNT proteins including regions in their C-terminus identified as hairpin and ... ...

Abstract	Wnt signaling is essential for embryonic development and tissue homeostasis. So far, little is known about the importance and functional relevance of the different regions in WNT proteins including regions in their C-terminus identified as hairpin and linker. However, it was shown that the C-terminus of WNT7A comprising the linker and the hairpin region is sufficient to elicit signaling. Here, we demonstrate that actually the hairpin region of WNT7A in its C-terminus is fully sufficient to induce non-canonical signaling in myogenic cells while the linker region alone did not show biological activity. Of note, all known non-canonical signaling branches of WNT7A signaling in skeletal muscle were activated by the hairpin region of WNT7A thereby inducing hypertrophy in myotubes, symmetric expansion of satellite stem cells and migration of myoblasts. Furthermore, we demonstrate that the linker region in the C-terminus of WNT7A binds to the FZD7 receptor while it does not activate non-canonical Wnt signaling. However, the hairpin and the linker region of WNT7A can activate canonical Wnt signaling independent of each other suggesting that specificity of downstream signaling might be depending on those specific regions in the C-terminus.
Language	English
Publishing date	2022-11-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.10.047
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Article: Wnt7a Counteracts Cancer Cachexia.

Schmidt, Manuel / Poser, Christine / von Maltzahn, Julia

Molecular therapy oncolytics

2020 Volume 16, Page(s) 134–146

Abstract: Cancer cachexia is a complex metabolic disease so far lacking effective therapy, and it accounts for approximately one third of all cancer-related deaths worldwide. The extracellular ligand Wnt7a has a dual function in skeletal muscle, inducing the ... ...

Abstract	Cancer cachexia is a complex metabolic disease so far lacking effective therapy, and it accounts for approximately one third of all cancer-related deaths worldwide. The extracellular ligand Wnt7a has a dual function in skeletal muscle, inducing the anabolic AKT/mammalian target of rapamycin (mTOR) pathway in myofibers and driving muscle stem cell expansion in skeletal muscle, making it a promising candidate for treatment of muscle wasting diseases. In murine and human myotubes, Wnt7a activates the anabolic AKT/mTOR pathway, thereby preventing cachexia-induced atrophy with a single application being sufficient to prevent atrophy independently of the tumor cell type causing cachexia. Addition of Wnt7a also improved activation and differentiation of muscle stem cells in cancer cachexia, a condition under which skeletal muscle regeneration is severely impaired due to stalled muscle stem cell differentiation. Finally, we show that Wnt7a prevents cancer cachexia in an
Language	English
Publishing date	2020-01-11
Publishing country	United States
Document type	Journal Article
ISSN	2372-7705
ISSN	2372-7705
DOI	10.1016/j.omto.2019.12.011
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Article ; Online: A dysfunctional miR-1-TRPS1-MYOG axis drives ERMS by suppressing terminal myogenic differentiation.

Hüttner, Sören S / Henze, Henriette / Elster, Dana / Koch, Philipp / Anderer, Ursula / von Eyss, Björn / von Maltzahn, Julia

Molecular therapy : the journal of the American Society of Gene Therapy

2023 Volume 31, Issue 9, Page(s) 2612–2632

Abstract: Rhabdomyosarcoma is the most common pediatric soft tissue tumor, comprising two major subtypes: the PAX3/7-FOXO1 fusion-negative embryonal and the PAX3/7-FOXO1 fusion-positive alveolar subtype. Here, we demonstrate that the expression levels of the ... ...

Abstract	Rhabdomyosarcoma is the most common pediatric soft tissue tumor, comprising two major subtypes: the PAX3/7-FOXO1 fusion-negative embryonal and the PAX3/7-FOXO1 fusion-positive alveolar subtype. Here, we demonstrate that the expression levels of the transcriptional repressor TRPS1 are specifically enhanced in the embryonal subtype, resulting in impaired terminal myogenic differentiation and tumor growth. During normal myogenesis, expression levels of TRPS1 have to decrease to allow myogenic progression, as demonstrated by overexpression of TRPS1 in myoblasts impairing myotube formation. Consequentially, myogenic differentiation in embryonal rhabdomyosarcoma in vitro as well as in vivo can be achieved by reducing TRPS1 levels. Furthermore, we show that TRPS1 levels in RD cells, the bona fide model cell line for embryonal rhabdomyosarcoma, are regulated by miR-1 and that TRPS1 and MYOD1 share common genomic binding sites. The myogenin (MYOG) promoter is one of the critical targets of TRPS1 and MYOD1; we demonstrate that TRPS1 restricts MYOG expression and thereby inhibits terminal myogenic differentiation. Therefore, reduction of TRPS1 levels in embryonal rhabdomyosarcoma might be a therapeutic approach to drive embryonal rhabdomyosarcoma cells into myogenic differentiation, thereby generating postmitotic myotubes.
MeSH term(s)	Humans ; Child ; Rhabdomyosarcoma, Embryonal/genetics ; Rhabdomyosarcoma, Embryonal/metabolism ; Rhabdomyosarcoma, Embryonal/pathology ; Myogenin/genetics ; Myogenin/metabolism ; Cell Differentiation/genetics ; MicroRNAs/genetics ; Muscle Development/genetics ; Cell Line, Tumor ; Repressor Proteins
Chemical Substances	Myogenin ; MicroRNAs ; TRPS1 protein, human ; Repressor Proteins ; MYOG protein, human ; MIRN1 microRNA, human
Language	English
Publishing date	2023-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2023.07.003
Database	MEDical Literature Analysis and Retrieval System OnLINE

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