scholarly journals Satellite Cell Depletion Disrupts Transcriptional Coordination and Muscle Adaptation to Exercise

Function ◽  
2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Davis A Englund ◽  
Vandré C Figueiredo ◽  
Cory M Dungan ◽  
Kevin A Murach ◽  
Bailey D Peck ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Gene Networks ◽  
Wheel Running ◽  
Skeletal Muscle Regeneration ◽  
Rna Seq ◽  
Muscle Adaptation ◽  
Hypertrophic Growth ◽  
Adaptation To Exercise

Abstract Satellite cells are required for postnatal development, skeletal muscle regeneration across the lifespan, and skeletal muscle hypertrophy prior to maturity. Our group has aimed to address whether satellite cells are required for hypertrophic growth in mature skeletal muscle. Here, we generated a comprehensive characterization and transcriptome-wide profiling of skeletal muscle during adaptation to exercise in the presence or absence of satellite cells in order to identify distinct phenotypes and gene networks influenced by satellite cell content. We administered vehicle or tamoxifen to adult Pax7-DTA mice and subjected them to progressive weighted wheel running (PoWeR). We then performed immunohistochemical analysis and whole-muscle RNA-seq of vehicle (SC+) and tamoxifen-treated (SC−) mice. Further, we performed single myonuclear RNA-seq to provide detailed information on how satellite cell fusion affects myonuclear transcription. We show that while skeletal muscle can mount a robust hypertrophic response to PoWeR in the absence of satellite cells, growth, and adaptation are ultimately blunted. Transcriptional profiling reveals several gene networks key to muscle adaptation are altered in the absence of satellite cells.

scholarly journals Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington's disease

2022 ◽  
Author(s):  
Sanzana Hoque ◽  
Marie Sjogren ◽  
Valerie Allamand ◽  
Kinga Gawlik ◽  
Naomi Franke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Muscle Damage ◽  
Satellite Cell ◽  
Mouse Models ◽  
Satellite Cells ◽  
Muscle Fibers ◽  
Cag Repeat ◽  
Skeletal Muscle Regeneration

Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

scholarly journals Depletion of resident muscle stem cells negatively impacts running volume, physical function, and muscle fiber hypertrophy in response to lifelong physical activity

2020 ◽  
Vol 318 (6) ◽  
pp. C1178-C1188 ◽  
Author(s):  
Davis A. Englund ◽  
Kevin A. Murach ◽  
Cory M. Dungan ◽  
Vandré C. Figueiredo ◽  
Ivan J. Vechetti ◽  
...  
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Physical Function ◽  
Satellite Cell ◽  
Muscle Fiber ◽  
Satellite Cells ◽  
Cell Depletion ◽  
Muscle Adaptation ◽  
Adult Skeletal Muscle

To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a nontranslational stimulus and/or have been performed over a relatively short time frame. Although it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long-term physical activity. The current study was designed to determine whether reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-diphtheria toxin A (DTA) mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 mo. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume, and the size of muscle proprioceptors (spindle fibers). Furthermore, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of G protein-coupled receptor (GPCR) signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long-term physical activity. These findings suggest that satellite cells play a role in preserving physical function during aging and influence muscle adaptation during sustained periods of physical activity.

Single-fiber isolation and maintenance of satellite cell quiescence

2005 ◽  
Vol 83 (5) ◽  
pp. 674-676 ◽  
Author(s):  
Ashley C Wozniak ◽  
Judy E Anderson
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Fibers ◽  
Single Fiber ◽  
Skeletal Muscle Regeneration ◽  
Mouse Muscle ◽  
Collagenase Digestion ◽  
Cell Quiescence ◽  
Gentle Agitation

The activity of satellite cells during myogenesis, development, or skeletal muscle regeneration is strongly modelled using cultures of single muscle fibers. However, there are variations in reported features of gene or protein expression as examined with single-fiber cultures. Here, we examined the potential differences in activation of satellite cells on normal mouse muscle fibers produced during a standard isolation protocol, with or without agitation during collagenase digestion. Activation was detected in satellite cells on fibers after 24 and 48 h of culture in basal growth medium using immunodetection of the incorporation of bromodeoxyuridine (BrdU) into DNA and quantification of the number of BrdU-positive cells per fiber. After 24 and 48 h in culture under nonactivating conditions, the number of activated (BrdU+) satellite cells was greater on fibers that had received gentle agitation during collagenase digestion than on those that were subject to digestion without agitation during isolation. The findings are interpreted to mean that at least some of the variation among published reports may derive from the application of various methods of fiber isolation. The information should be useful for maintaining satellite cell quiescence during studies of the regulatory steps that lead to satellite cell activation.Key words: activation, skeletal muscle, proliferation, single-fiber culture, myogenesis.

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

2018 ◽  
Vol 11 (1) ◽  
pp. 53-66 ◽  
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.

Inactivation of PPARβ/δ adversely affects satellite cells and reduces postnatal myogenesis

2015 ◽  
Vol 309 (2) ◽  
pp. E122-E131 ◽  
Author(s):  
Preeti Chandrashekar ◽  
Ravikumar Manickam ◽  
Xiaojia Ge ◽  
Sabeera Bonala ◽  
Craig McFarlane ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Tibialis Anterior ◽  
Tibialis Anterior Muscle ◽  
Skeletal Muscle Regeneration ◽  
Muscle Weight ◽  
Cross Sectional ◽  
Postnatal Myogenesis

Peroxisome proliferator-activated receptor β/δ ( PPARβ/δ) is a ubiquitously expressed gene with higher levels observed in skeletal muscle. Recently, our laboratory showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935–12951, 2012) that PPARβ/δ modulates myostatin activity to induce myogenesis in skeletal muscle. In the present study, we show that PPARβ/δ-null mice display reduced body weight, skeletal muscle weight, and myofiber atrophy during postnatal development. In addition, a significant reduction in satellite cell number was observed in PPARβ/δ-null mice, suggesting a role for PPARβ/δ in muscle regeneration. To investigate this, tibialis anterior muscles were injured with notexin, and muscle regeneration was monitored on days 3, 5, 7, and 28 postinjury. Immunohistochemical analysis revealed an increased inflammatory response and reduced myoblast proliferation in regenerating muscle from PPARβ/δ-null mice. Histological analysis confirmed that the regenerated muscle fibers of PPARβ/δ-null mice maintained an atrophy phenotype with reduced numbers of centrally placed nuclei. Even though satellite cell numbers were reduced before injury, satellite cell self-renewal was found to be unaffected in PPARβ/δ-null mice after regeneration. Previously, our laboratory had showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935–12951, 2012) that inactivation of PPARβ/δ increases myostatin signaling and inhibits myogenesis. Our results here indeed confirm that inactivation of myostatin signaling rescues the atrophy phenotype and improves muscle fiber cross-sectional area in both uninjured and regenerated tibialis anterior muscle from PPARβ/δ-null mice. Taken together, these data suggest that absence of PPARβ/δ leads to loss of satellite cells, impaired skeletal muscle regeneration, and postnatal myogenesis. Furthermore, our results also demonstrate that functional antagonism of myostatin has utility in rescuing these effects.

Xin, an actin binding protein, is expressed within muscle satellite cells and newly regenerated skeletal muscle fibers

2007 ◽  
Vol 293 (5) ◽  
pp. C1636-C1644 ◽  
Author(s):  
Thomas J. Hawke ◽  
Daniel J. Atkinson ◽  
Shane B. Kanatous ◽  
Peter F. M. Van der Ven ◽  
Sean C. Goetsch ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Myogenic Differentiation ◽  
Binding Protein ◽  
Skeletal Muscle Regeneration ◽  
Actin Binding ◽  
Skeletal Muscle Myosin ◽  
Muscle Satellite Cells ◽  
Actin Binding Protein

Xin is a muscle-specific actin binding protein of which its role and regulation within skeletal muscle is not well understood. Here we demonstrate that Xin mRNA is robustly upregulated (>16-fold) within 12 h of skeletal muscle injury and is localized to the muscle satellite cell population. RT-PCR confirmed the expression pattern of Xin during regeneration, as well as within primary muscle myoblast cultures, but not other known stem cell populations. Immunohistochemical staining of single myofibers demonstrate Xin expression colocalized with the satellite cell marker Syndecan-4 further supporting the mRNA expression of Xin in satellite cells. In situ hybridization of regenerating muscle 5–7 days postinjury illustrates Xin expression within newly regenerated myofibers. Promoter-reporter assays demonstrate that known myogenic transcription factors [myocyte enhancer factor-2 (MEF2), myogenic differentiation-1 (MyoD), and myogenic factor-5 (Myf-5)] transactivate Xin promoter constructs supporting the muscle-specific expression of Xin. To determine the role of Xin within muscle precursor cells, proliferation, migration, and differentiation analysis using Xin, short hairpin RNA (shRNA) were undertaken in C2C12 myoblasts. Reducing endogenous Xin expression resulted in a 26% increase ( P < 0.05) in cell proliferation and a 20% increase ( P < 0.05) in myoblast migratory capacity. Skeletal muscle myosin heavy chain protein levels were increased ( P < 0.05) with Xin shRNA administration; however, this was not accompanied by changes in myoglobin protein (another marker of differentiation) nor overt morphological differences relative to differentiating control cells. Taken together, the present findings support the hypothesis that Xin is expressed within muscle satellite cells during skeletal muscle regeneration and is involved in the regulation of myoblast function.

scholarly journals Loss of the adipokine lipocalin-2 impairs satellite cell activation and skeletal muscle regeneration

2018 ◽  
Vol 315 (5) ◽  
pp. C714-C721 ◽  
Author(s):  
Irena A. Rebalka ◽  
Cynthia M. F. Monaco ◽  
Nina E. Varah ◽  
Thorsten Berger ◽  
Donna M. D’souza ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Cell Activation ◽  
Skeletal Muscle Regeneration ◽  
Matrix Remodeling ◽  
Muscle Repair ◽  
Lipocalin 2 ◽  
The Impact

Lipocalin-2 (LCN2) is an adipokine previously described for its contribution to numerous processes, including innate immunity and energy metabolism. LCN2 has also been demonstrated to be an extracellular matrix (ECM) regulator through its association with the ECM protease matrix metalloproteinase-9 (MMP-9). With the global rise in obesity and the associated comorbidities related to increasing adiposity, it is imperative to gain an understanding of the cross talk between adipose tissue and other metabolic tissues, such as skeletal muscle. Given the function of LCN2 on the ECM in other tissues and the importance of matrix remodeling in skeletal muscle regeneration, we examined the localization and expression of LCN2 in uninjured and regenerating wild-type skeletal muscle and assessed the impact of LCN2 deletion (LCN2−/−) on skeletal muscle repair following cardiotoxin injury. Though LCN2 was minimally present in uninjured skeletal muscle, its expression was increased significantly at 1 and 2 days postinjury, with expression present in Pax7-positive satellite cells. Although satellite cell content was unchanged, the ability of quiescent satellite cells to become activated was significantly impaired in LCN2−/− skeletal muscles. Skeletal muscle regeneration was also significantly compromised as evidenced by decreased embryonic myosin heavy chain expression and smaller regenerating myofiber areas. Consistent with a role for LCN2 in MMP-9 regulation, regenerating muscle also displayed a significant increase in fibrosis and lower ( P = 0.07) MMP-9 activity in LCN2−/− mice at 2 days postinjury. These data highlight a novel role for LCN2 in muscle regeneration and suggest that changes in adipokine expression can significantly impact skeletal muscle repair.

scholarly journals The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Guangyan Xiong ◽  
Sajedah M Hindi ◽  
Aman K Mann ◽  
Yann S Gallot ◽  
Kyle R Bohnert ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Unfolded Protein Response ◽  
Satellite Cell ◽  
P38 Mapk ◽  
Satellite Cells ◽  
Skeletal Muscle Regeneration ◽  
Unfolded Protein ◽  
Protein Response

Regeneration of skeletal muscle in adults is mediated by satellite stem cells. Accumulation of misfolded proteins triggers endoplasmic reticulum stress that leads to unfolded protein response (UPR). The UPR is relayed to the cell through the activation of PERK, IRE1/XBP1, and ATF6. Here, we demonstrate that levels of PERK and IRE1 are increased in satellite cells upon muscle injury. Inhibition of PERK, but not the IRE1 arm of the UPR in satellite cells inhibits myofiber regeneration in adult mice. PERK is essential for the survival and differentiation of activated satellite cells into the myogenic lineage. Deletion of PERK causes hyper-activation of p38 MAPK during myogenesis. Blocking p38 MAPK activity improves the survival and differentiation of PERK-deficient satellite cells in vitro and muscle formation in vivo. Collectively, our results suggest that the PERK arm of the UPR plays a pivotal role in the regulation of satellite cell homeostasis during regenerative myogenesis.

scholarly journals Depletion of resident muscle stem cells inhibits muscle fiber hypertrophy induced by lifelong physical activity

2019 ◽  
Author(s):  
Davis A. Englund ◽  
Kevin A. Murach ◽  
Cory M. Dungan ◽  
Vandré C. Figueiredo ◽  
Ivan J. Vechetti ◽  
...  
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Physical Function ◽  
Satellite Cell ◽  
Muscle Fiber ◽  
Satellite Cells ◽  
Muscle Growth ◽  
Free Access ◽  
Running Wheel ◽  
Hypertrophic Growth

AbstractBackgroundA reduction in skeletal muscle stem cell (satellite cell) content with advancing age is thought to directly contribute to the progressive loss of skeletal muscle mass and function with aging (sarcopenia). However, we reported that the depletion of satellite cells throughout adulthood did not affect the onset or degree of sarcopenia observed in sedentary old mice. The current study was designed to determine if lifelong physical activity would alter the requirements for satellite cells during aging.MethodsWe administered vehicle or tamoxifen to adult (5 months old) female Pax7-DTA mice for 5 consecutive days to effectively deplete satellite cells. Following a 2-month washout period, mice were assigned to physically active (free access to a running wheel) or sedentary (locked running wheel) conditions. Thirteen months later, at a mean age of 20 months, mice were sacrificed for subsequent analysis.ResultsSatellite cell depletion throughout adulthood negatively impacted physical function and limited muscle fiber hypertrophy in response to lifelong physical activity. To further interrogate these findings, we performed transcriptome-wide analyses on the hind limb muscles that experienced hypertrophic growth (plantaris and soleus) in response to lifelong physical activity. Our findings demonstrate that satellite cell function is muscle type-specific; fusion with fibers is apparent in oxidative muscles, while initiation of Gαi2 signaling appears to require satellite cells in glycolytic muscles to induce muscle growth..ConclusionsThese findings suggest that satellite cells, or their secretory products, are viable therapeutic targets to preserve physical function with aging and promote muscle growth in older adults who regularly engage in physical activity.

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