Lack of evidence for GDF11 as a rejuvenator of aged skeletal muscle satellite cells.
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ABSTRACT:
SUBMITTER: Hinken AC
PROVIDER: S-EPMC4854912 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epigenetic alterations occur in various cells and tissues during aging, but it is not known if such alterations are also associated with aging in skeletal muscle. Here, we examined the changes of a panel of histone modifications and found H3K27ac (an active enhancer mark) is markedly increased in aged human skeletal muscle tissues. Further analyses uncovered that the H3K27ac increase and enhancer activation are associated with the up-regulation of extracellular matrix (ECM) genes; this may result in alteration of the niche environment for skeletal muscle stem cells, also called satellite cells (SCs), which causes decreased myogenic potential and fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, inhibited the ECM up-regulation and fibrogenic conversion of SCs and restored their myogenic differentiation potential. Altogether, our findings not only uncovered a novel aspect of skeletal muscle aging that is associated with enhancer remodeling but also implicated JQ1 as a potential treatment approach for restoring SC function in aging muscle.
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Project description:Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-? molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.
| S-EPMC4497834 | biostudies-literature
Project description:BackgroundGrowth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily. The GDF11 propeptide, which is derived from the GDF11 precursor protein, blocks the activity of GDF11 and its homolog, myostatin, which are both potent inhibitors of muscle growth. Thus, treatment with GDF11 propeptide may be a potential therapeutic strategy for diseases associated with muscle atrophy like sarcopenia and the muscular dystrophies. Here, we evaluate the impact of GDF11 propeptide-Fc (GDF11PRO-Fc) gene delivery on skeletal muscle in normal and dystrophic adult mice.MethodsA pull-down assay was used to obtain physical confirmation of a protein-protein interaction between GDF11PRO-Fc and GDF11 or myostatin. Next, differentiated C2C12 myotubes were treated with AAV6-GDF11PRO-Fc and challenged with GDF11 or myostatin to determine if GDF11PRO-Fc could block GDF11/myostatin-induced myotube atrophy. Localized expression of GDF11PRO-Fc was evaluated via a unilateral intramuscular injection of AAV9-GDF11PRO-Fc into the hindlimb of C57BL/6J mice. In mdx mice, intravenous injection of AAV9-GDF11PRO-Fc was used to achieve systemic expression. The impact of GDF11PRO-Fc on muscle mass, function, and pathological features were assessed.ResultsGDF11PRO-Fc was observed to bind both GDF11 and myostatin. In C2C12 myotubes, expression of GDF11PRO-Fc was able to mitigate GDF11/myostatin-induced atrophy. Following intramuscular injection in C57BL/6J mice, increased grip strength and localized muscle hypertrophy were observed in the injected hindlimb after 10 weeks. In mdx mice, systemic expression of GDF11PRO-Fc resulted in skeletal muscle hypertrophy without a significant change in cardiac mass after 12 weeks. In addition, grip strength and rotarod latency time were improved. Intramuscular fibrosis was also reduced in treated mdx mice; however, there was no change seen in central nucleation, membrane permeability to serum IgG or serum creatine kinase levels.ConclusionsGDF11PRO-Fc induces skeletal muscle hypertrophy and improvements in muscle strength via inhibition of GDF11/myostatin signaling. However, GDF11PRO-Fc does not significantly improve the dystrophic pathology in mdx mice.
| S-EPMC6537384 | biostudies-literature
Project description:Satellite cells are tissue-specific stem cells responsible for skeletal muscle growth and regeneration. Although satellite cells were identified almost 50 years ago, the identity of progenitor populations from which they derive remains controversial. We developed MyoD(iCre) knockin mice, and used Cre/lox lineage analysis to determine whether satellite cell progenitors express MyoD, a marker of myogenic commitment. Recombination status of satellite cells was determined by confocal microscopy of isolated muscle fibers and by electron microscopic observation of muscle tissue fixed immediately following isolation, using R26R-EYFP and R26R (beta-gal) reporter mice, respectively. We show that essentially all adult satellite cells associated with limb and body wall musculature, as well as the diaphragm and extraocular muscles, originate from MyoD+ progenitors. Neonatal satellite cells were Cre-recombined, but only a small minority exhibited ongoing Cre expression, indicating that most satellite cells had expressed MyoD prenatally. We also show that satellite cell development in MyoD-null mice is not due to functional compensation by MyoD non-expressing lineages. The results suggest that satellite cells are derived from committed myogenic progenitors, irrespective of the anatomical location, embryological origin, or physiological properties of associated musculature.
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Project description:Regeneration and repair of skeletal muscle is driven by tissue-specific progenitor cells called satellite cells, which occupy a minority of the cells in the muscle. This protocol provides researchers with techniques to efficiently isolate and purify functional satellite cells from human muscle tissue. The proven techniques described here enable the preparation of purified and minimally altered satellite cells for in vitro and in vivo experimentation and for potential clinical applications. For complete details on the use and execution of this protocol, please refer to Barruet et al. (2020) and Garcia et al. (2018).
| S-EPMC7851841 | biostudies-literature
Project description:Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.
| S-EPMC5833306 | biostudies-literature
Project description:A variety of epigenetic alterations impairs functions of cells and tissues during aging, but it is not known if epigenetic alterations are associated with aging muscle. Here, we examined the changes of a panel of histone marks and found H3K27ac (an active enhancer mark) is markedly increased during aging in human skeletal muscle tissues. Our integrated analysis showed that enhancer activation during muscle aging is associated with the up-regulation of extracelluar matrix (ECM) genes, which may result in stiffness of the niche environment of satellite cells (SCs). An age-related fibrogenic conversion of geriatric SCs was observed through differential gene expression analysis. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation reverted the ECM up-regulation and fibrogenic conversion of SCs, suggesting that ECM increase in aging muscle is indeed a result of enhancer activation. The study here not only uncovered a novel aspect of muscle aging that is associated with enhancer remodeling but also highlighted JQ1 as a potential treatment approach for restoring SC function in aging muscle.
2019-08-15 | GSE122867 | GEO
Project description:Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.
| S-EPMC5824957 | biostudies-literature
Project description:Changes in satellite cell content play a key role in regulating skeletal muscle growth and atrophy. Yet, there is little information on changes in satellite cell content from birth to old age in humans. The present study defines muscle fiber type-specific satellite cell content in human skeletal muscle tissue over the entire lifespan. Muscle biopsies were collected in 165 subjects, from different muscles of children undergoing surgery (<18 years; n?=?13) and from the vastus lateralis muscle of young adult (18–49 years; n?=?50), older (50–69 years; n?=?53), and senescent subjects (70–86 years; n?=?49). In a subgroup of 51 aged subjects (71?±?6 years), additional biopsies were collected after 12 weeks of supervised resistance-type exercise training. Immunohistochemistry was applied to assess skeletal muscle fiber type-specific composition, size, and satellite cell content. From birth to adulthood, muscle fiber size increased tremendously with no major changes in muscle fiber satellite cell content, and no differences between type I and II muscle fibers. In contrast to type I muscle fibers, type II muscle fiber size was substantially smaller with increasing age in adults (r?=??0.56; P?<?0.001). This was accompanied by an age-related reduction in type II muscle fiber satellite cell content (r?=??0.57; P?<?0.001). Twelve weeks of resistance-type exercise training significantly increased type II muscle fiber size and satellite cell content. We conclude that type II muscle fiber atrophy with aging is accompanied by a specific decline in type II muscle fiber satellite cell content. Resistance-type exercise training represents an effective strategy to increase satellite cell content and reverse type II muscle fiber atrophy.
| S-EPMC4039250 | biostudies-literature
Project description:Skeletal muscle can repair and regenerate due to resident stem cells known as satellite cells. The muscular dystrophies are progressive muscle wasting diseases underscored by chronic muscle damage that is continually repaired by satellite cell-driven regeneration. Here we generate a genetic strategy to mediate satellite cell ablation in dystrophic mouse models to investigate how satellite cells impact disease trajectory. Unexpectedly, we observe that depletion of satellite cells reduces dystrophic disease features, with improved histopathology, enhanced sarcolemmal stability and augmented muscle performance. Mechanistically, we demonstrate that satellite cells initiate expression of the myogenic transcription factor MyoD, which then induces re-expression of fetal genes in the myofibers that destabilize the sarcolemma. Indeed, MyoD re-expression in wildtype adult skeletal muscle reduces membrane stability and promotes histopathology, while MyoD inhibition in a mouse model of muscular dystrophy improved membrane stability. Taken together these observations suggest that satellite cell activation and the fetal gene program is maladaptive in chronic dystrophic skeletal muscle.
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