Satellite cell depletion in early adulthood attenuates muscular dystrophy pathogenesis

AbstractSatellite cells are skeletal muscle resident stem cells that regenerate adult myofibers following an acute injury to muscle. Despite the assumption that the loss of satellite cells would be detrimental in a chronic regeneration-inducing muscle disease such as muscular dystrophy, this assumption has never been tested using mouse genetics. Here we generated a novel model of satellite cell ablation and crossed it with mouse models of muscular dystrophy to directly investigate how critical these cells are in maintaining muscle during a chronic degenerative disorder. Satellite cell deletion in 2-week-old young dystrophic mice provided noticeable improvements in histopathology and function, although at this early timepoint it was utimately detrimental because muscle size was not sufficient to permit survival. However, depletion of satellite cells beginning at 2 months of age in dystrophic mice provided similar histological and functional improvements but without compromising muscle size. The improved profile showed fewer damaged fibers, less myofiber central nucleation, increased sarcolemma integrity, decreased fibrosis and a dramatic size increase in the remaining myofibers. At the functional level, young adult dystrophic mice lacking satellite cells performed significantly better than those with satellite cells when exercised on a treadmill. Thus, loss of satellite cells during early adulthood in dystrophic mice produces an unexpected protective effect.

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Stem cells for skeletal muscle repair

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2011.0027 ◽

2011 ◽

Vol 366 (1575) ◽

pp. 2297-2306 ◽

Cited By ~ 63

Author(s):

Jennifer L. Shadrach ◽

Amy J. Wagers

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Satellite Cell ◽

Satellite Cells ◽

Cell Function ◽

Therapeutic Potential ◽

Muscle Disease ◽

Muscle Fibres ◽

Muscle Repair ◽

Muscle Satellite Cells

Skeletal muscle is a highly specialized tissue composed of non-dividing, multi-nucleated muscle fibres that contract to generate force in a controlled and directed manner. Skeletal muscle is formed during embryogenesis from a subset of muscle precursor cells, which generate both differentiated muscle fibres and specialized muscle-forming stem cells known as satellite cells. Satellite cells remain associated with muscle fibres after birth and are responsible for muscle growth and repair throughout life. Failure in satellite cell function can lead to delayed, impaired or failed recovery after muscle injury, and such failures become increasingly prominent in cases of progressive muscle disease and in old age. Recent progress in the isolation of muscle satellite cells and elucidation of the cellular and molecular mediators controlling their activity indicate that these cells represent promising therapeutic targets. Such satellite cell-based therapies may involve either direct cell replacement or development of drugs that enhance endogenous muscle repair mechanisms. Here, we discuss recent breakthroughs in understanding both the cell intrinsic and extrinsic regulators that determine the formation and function of muscle satellite cells, as well as promising paths forward to realizing their full therapeutic potential.

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Female Outperformance in Voluntary Running Persists in Dystrophin-Null and Klotho-Overexpressing Mice

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210703 ◽

2021 ◽

pp. 1-11

Author(s):

Michael Phelps ◽

Zipora Yablonka-Reuveni

Keyword(s):

Wheel Running ◽

Dystrophin Gene ◽

Muscle Disease ◽

Mouse Strains ◽

Male Mice ◽

Wild Type ◽

Running Performance ◽

Voluntary Running ◽

And Function ◽

Dystrophic Mice

Background: Duchenne muscular dystrophy is a degenerative muscle disease that results from impairment of the dystrophin gene. The disease causes progressive loss in muscle mass and function. Objective: The anti-aging protein, α-klotho, has been implicated in the regulation of muscle regeneration. We previously discovered that mice harboring reduced α-klotho levels exhibited a decline in muscle strength and running endurance. Method: To investigate the ability of α-klotho to improve overall endurance in a dystrophin null murine model, we examined the voluntary wheel running performance of dystrophin-null, mdx4cv mice overexpressing an α-klotho transgene. Results: As expected, compared to wild type, both male and female dystrophic mice exhibited reduced running ability that was characterized by shorter running duration and longer periods of rest between cycles of activity. While our results did not detect an improvement in running performance with α-klotho overexpression, we identified distinct differences in the running patterns between females and males from all mouse strains analyzed (i.e., mdx4cv, mdx4cv overexpressing α-klotho, α-klotho overexpressing, α-klotho hypomorph, and wild type). For all strains, male mice displayed significantly reduced voluntary running ability compared to females. Further analysis of the mdx4cv strains demonstrated that male mice ran for shorter lengths of time and took longer breaks. However, we did not identify gender-associated differences in the actual speed at which mdx4cv mice ran. Conclusion: Our data suggest key differences in the running capabilities of female and male mice, which are of particularly relevant to studies of dystrophin-null mice.

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Tetraspanin CD82 is necessary for muscle stem cell activation and supports dystrophic muscle function

Skeletal Muscle ◽

10.1186/s13395-020-00252-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Arielle Hall ◽

Tatiana Fontelonga ◽

Alec Wright ◽

Katlynn Bugda Gwilt ◽

Jeffrey Widrick ◽

...

Keyword(s):

Muscular Dystrophy ◽

Satellite Cell ◽

Muscle Function ◽

Regulatory Networks ◽

Cell Activation ◽

Cell Activity ◽

Compensatory Mechanism ◽

Dystrophic Muscle ◽

Functional Link ◽

Dystrophic Mice

Abstract Background Tetraspanins are a family of proteins known to assemble protein complexes at the cell membrane. They are thought to play diverse cellular functions in tissues by modifying protein-binding partners, thus bringing complexity and diversity in their regulatory networks. Previously, we identified the tetraspanin KAI/CD82 as a prospective marker for human muscle stem cells. CD82 expression appeared decreased in human Duchenne muscular dystrophy (DMD) muscle, suggesting a functional link to muscular dystrophy, yet whether this decrease is a consequence of dystrophic pathology or a compensatory mechanism in an attempt to rescue muscle from degeneration is currently unknown. Methods We studied the consequences of loss of CD82 expression in normal and dystrophic skeletal muscle and examined the dysregulation of downstream functions in mice aged up to 1 year. Results Expression of CD82 is important to sustain satellite cell activation, as in its absence there is decreased cell proliferation and less efficient repair of injured muscle. Loss of CD82 in dystrophic muscle leads to a worsened phenotype compared to control dystrophic mice, with decreased pulmonary function, myofiber size, and muscle strength. Mechanistically, decreased myofiber size in CD82−/− dystrophic mice is not due to altered PTEN/AKT signaling, although increased phosphorylation of mTOR at Ser2448 was observed. Conclusion Basal CD82 expression is important to dystrophic muscle, as its loss leads to significantly weakened myofibers and impaired muscle function, accompanied by decreased satellite cell activity that is unable to protect and repair myofiber damage.

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Canonical NF-κB signaling regulates satellite stem cell homeostasis and function during regenerative myogenesis

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjy053 ◽

2018 ◽

Vol 11 (1) ◽

pp. 53-66 ◽

Cited By ~ 3

Author(s):

Alex R Straughn ◽

Sajedah M Hindi ◽

Guangyan Xiong ◽

Ashok Kumar

Keyword(s):

Skeletal Muscle ◽

Satellite Cell ◽

Satellite Cells ◽

Muscle Regeneration ◽

Cell Function ◽

Skeletal Muscle Regeneration ◽

Cell Homeostasis ◽

Adult Skeletal Muscle ◽

Adult Mice ◽

And Function

Abstract Skeletal muscle regeneration in adults is attributed to the presence of satellite stem cells that proliferate, differentiate, and eventually fuse with injured myofibers. However, the signaling mechanisms that regulate satellite cell homeostasis and function remain less understood. While IKKβ-mediated canonical NF-κB signaling has been implicated in the regulation of myogenesis and skeletal muscle mass, its role in the regulation of satellite cell function during muscle regeneration has not been fully elucidated. Here, we report that canonical NF-κB signaling is induced in skeletal muscle upon injury. Satellite cell-specific inducible ablation of IKKβ attenuates skeletal muscle regeneration in adult mice. Targeted ablation of IKKβ also reduces the number of satellite cells in injured skeletal muscle of adult mice, potentially through inhibiting their proliferation and survival. We also demonstrate that the inhibition of specific components of the canonical NF-κB pathway causes precocious differentiation of cultured satellite cells both ex vivo and in vitro. Finally, our results highlight that the constitutive activation of canonical NF-κB signaling in satellite cells also attenuates skeletal muscle regeneration following injury in adult mice. Collectively, our study demonstrates that the proper regulation of canonical NF-κB signaling is important for the regeneration of adult skeletal muscle.

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Chloroquine Decreases Cardiomyocyte Autophagy and Improves Cardiac Function in a Mouse Model of Duchenne Muscular Dystrophy

10.21203/rs.3.rs-149383/v1 ◽

2021 ◽

Author(s):

Takaya Hirata ◽

Shiro Baba ◽

Kentaro Akagi ◽

Daisuke Yoshinaga ◽

Katsutsugu Umeda ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Left Ventricular ◽

Muscle Disease ◽

Therapeutic Modality ◽

Cardiomyocyte Autophagy ◽

And Function ◽

Ventricle Size

Abstract Background: Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes. Methods: In the present study, we demonstrated that autophagy was enhanced in the cardiomyocytes of mdx mice, a model of DMD, and that increased autophagy contributed to the development of cardiomyopathy in this context. Results: As assessed by GFP-mRFP-LC3 transfection, autophagosomes were more abundant in cardiomyocytes of mdx mice compared with control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by isoproterenol-induced cardiac stress (4 weeks) in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine, an autophagy inhibitor, significantly decreased cardiomyocyte autophagy and fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration.Conclusions: These findings suggested that heart failure of DMD could be associated with autophagy. Therefore, autophagy inhibitors, such as chloroquine, are a potential therapeutic modality for heart failure in DMD patients.

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Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis

The Journal of Cell Biology ◽

10.1083/jcb.200508001 ◽

2006 ◽

Vol 172 (1) ◽

pp. 103-113 ◽

Cited By ~ 290

Author(s):

Shihuan Kuang ◽

Sophie B. Chargé ◽

Patrick Seale ◽

Michael Huh ◽

Michael A. Rudnicki

Keyword(s):

Satellite Cell ◽

Satellite Cells ◽

Muscle Regeneration ◽

Messenger Rna ◽

Hind Limb ◽

Muscle Wasting ◽

Cell Lineage ◽

Acute Injury ◽

Limb Muscle ◽

Hind Limb Muscle

We assessed viable Pax7−/− mice in 129Sv/J background and observed reduced growth and marked muscle wasting together with a complete absence of functional satellite cells. Acute injury resulted in an extreme deficit in muscle regeneration. However, a small number of regenerated myofibers were detected, suggesting the presence of residual myogenic cells in Pax7-deficient muscle. Rare Pax3+/MyoD+ myoblasts were recovered from Pax7−/− muscle homogenates and cultures of myofiber bundles but not from single myofibers free of interstitial tissues. Finally, we identified Pax3+ cells in the muscle interstitial environment and demonstrated that they coexpressed MyoD during regeneration. Sublaminar satellite cells in hind limb muscle did not express detectable levels of Pax3 protein or messenger RNA. Therefore, we conclude that interstitial Pax3+ cells represent a novel myogenic population that is distinct from the sublaminar satellite cell lineage and that Pax7 is essential for the formation of functional myogenic progenitors from sublaminar satellite cells.

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Androgen regulation of satellite cell function

Journal of Endocrinology ◽

10.1677/joe.1.05976 ◽

2005 ◽

Vol 186 (1) ◽

pp. 21-31 ◽

Cited By ~ 72

Author(s):

Yue Chen ◽

Jeffrey D Zajac ◽

Helen E MacLean

Keyword(s):

Satellite Cell ◽

Satellite Cells ◽

Cell Activation ◽

Cell Function ◽

Dependent Manner ◽

Androgen Treatment ◽

Androgen Action ◽

Androgen Regulation ◽

And Function

Androgen treatment can enhance the size and strength of muscle. However, the mechanisms of androgen action in skeletal muscle are poorly understood. This review discusses potential mechanisms by which androgens regulate satellite cell activation and function. Studies have demonstrated that androgen administration increases satellite cell numbers in animals and humans in a dose–dependent manner. Moreover, androgens increase androgen receptor levels in satellite cells. In vitro, the results are contradictory as to whether androgens regulate satellite cell proliferation or differentiation. IGF-I is one major target of androgen action in satellite cells. In addition, the possibility of non-genomic actions of androgens on satellite cells is discussed. In summary, this review focuses on exploring potential mechanisms through which androgens regulate satellite cells, by analyzing developments from research in this area.

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Phospholipid composition and metabolism in mouse muscular dystrophy

Biochemical Journal ◽

10.1042/bj1760015 ◽

1978 ◽

Vol 176 (1) ◽

pp. 15-22 ◽

Cited By ~ 27

Author(s):

Chea T. Kwok ◽

Lawrence Austin

Keyword(s):

Spinal Cord ◽

Muscular Dystrophy ◽

Sciatic Nerve ◽

Phospholipid Composition ◽

Fold Increase ◽

Membrane Structure And Function ◽

Sciatic Nerves ◽

And Function ◽

Dystrophic Mice ◽

Phospholipases A

1. The composition and metabolism of phospholipids were studied in various tissues from both normal and dystrophic mice of the 129 ReJ strain. Phospholipids extracted from forebrain, spinal cord, sciatic nerve and plasma were fractionated by t.l.c. and measured. 2. Very significant alterations were found in the choline phospholipids from these tissues, except forebrain. Plasma phosphatidylcholine in the dystrophic mouse was increased by 38%. There was a 2-fold increase in lysophosphatidylcholine in the spinal cord of dystrophic mice. The sciatic nerve showed a marked decrease in sphingomyelin content, which is approximately half of that in the controls. 3. Five enzymes involved in phosphatidylcholine metabolism [namely cholinephosphotransferase (EC 2.7.8.2); phospholipases A (EC 3.1.1.4, EC 3.1.1.32); lysophospholipase (EC 3.1.1.5); lysophosphatidylcholine acyltransferase (EC 2.3.1.23); phospholipase C (EC 3.1.4.3)] were studied in tissue preparations from forebrain, spinal cord, sciatic nerves, gastrocnemius muscles and liver. 4. Activities of phospholipases A and C were significantly increased, about 5-fold and 60% respectively, in gastrocnemius muscle of dystrophic mice compared with controls. Phospholipases A also showed 50% higher activity in the sciatic nerves of dystrophic than of normal mice. Lysophosphatidylcholine acyltransferase activities were significantly increased in the sciatic nerves and spinal cord, by 50–100% over that of the controls. The forebrain and spinal cord from dystrophic mice, however, had only 60% of lysophospholipase activities of that of the normal control. Cholinephosphotransferase activity was unchanged in these tissues from both normal and dystrophic mice. 5. It is suggested that are number of features of mouse muscular dystrophy related to altered membrane structure and function can be rationalized in terms of changes in lipid composition and metabolism.

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POPDC proteins and cardiac function

Biochemical Society Transactions ◽

10.1042/bst20190249 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1393-1404 ◽

Cited By ~ 4

Author(s):

Thomas Brand

Keyword(s):

Potential Role ◽

Striated Muscle ◽

Short Review ◽

Effector Proteins ◽

Muscle Disease ◽

Disease Genes ◽

Protein Protein Interaction ◽

Interaction Partners ◽

And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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