GDF11 Decreases Pressure Overload–Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death

Harper, Shavonn C.; Johnson, Jaslyn; Borghetti, Giulia; Zhao, Huaqing; Wang, Tao; Wallner, Markus; Kubo, Hajime; Feldsott, Eric; Yang, Yijun; Joo, Yunichel; Gou, Xinji; Sabri, Abdel Karim; Gupta, Priyanka; Myzithras, Maria; Khalil, Ashraf M.; Franti, Michael; Houser, Steven R.

doi:10.1161/circresaha.118.312955

Cited by 43 publications

(49 citation statements)

References 49 publications

(86 reference statements)

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“…As Gdf11 expression is upregulated is discrete immune cell lineages (Fig. 3A,B) and GDF11 functions in adulthood have previously been implicated in cardiac hypertrophy 37,67–69 , erythropoiesis 70,71 , and skeletal muscle biology 39,40 , we focused our analyses on the heart, skeletal muscle, and immune organs. We did not detect significant differences in body weight (Fig.…”

Section: Resultsmentioning

confidence: 99%

Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus

Goldstein

Valido

Lewandowski

et al. 2019

Sci Rep

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Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to generate a knock-in GFP reporter mouse at the Gdf11 locus. Phenotypic and genomic characterization of founder animals from these injections revealed a subset that contained the correct targeting event and exhibited GFP expression that, within the hematopoietic system, was restricted predominantly to lymphoid cells. Yet, in another subset of founder mice, we detected aberrant integration events at the target site that dramatically and inaccurately shifted hematopoietic GFP expression from the lymphoid to the myeloid lineage. Additionally, we recovered multiple Gdf11 deletion alleles that modified the C-terminus of the GDF11 protein. When bred to homozygosity, most of these alleles recapitulated skeletal phenotypes reported previously for Gdf11 knockout mice, suggesting that these represent null alleles. However, we also recovered one Gdf11 deletion allele that encodes a novel GDF11 variant protein (“GDF11-WE”) predicted to contain two additional amino acids (tryptophan (W) and glutamic acid (E)) at the C-terminus of the mature ligand. Unlike the other Gdf11 deletion alleles recovered in this study, homozygosity for the Gdf11WE allele did not phenocopy Gdf11 knockout skeletal phenotypes. Further investigation using in vivo and in vitro approaches demonstrated that GDF11-WE retains substantial physiological function, indicating that GDF11 can tolerate at least some modifications of its C-terminus and providing unexpected insights into its biochemical activities. Altogether, our study confirms that one-step zygotic injections of CRISPR/Cas gene editing complexes provide a quick and powerful tool to generate gene-modified mouse models. Moreover, our findings underscore the critical importance of thorough characterization and validation of any modified alleles generated by CRISPR, as unintended on-target effects that fail to be detected by simple PCR screening can produce substantially altered phenotypic readouts.

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Section: Resultsmentioning

confidence: 99%

Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus

Goldstein

Valido

Lewandowski

et al. 2019

Sci Rep

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“…Importantly, our experimental design and rGDF11 dosing regimen did not cause premature death during the experimental timeframe, did not cause anorexia, and did not result in a cachectic phenotype. It is possible that these effects may arise using a substantially-higher dose or alternative method of overexpression of GDF11 11,[13][14][15] . We cannot exclude the possibility that using higher rGDF8 doses in the same experimental design would induce metabolic phenotypes comparable to those seen with rGDF11.…”

Section: Discussionmentioning

confidence: 99%

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice

Walker

Barrandon

Poggioli

et al. 2020

Sci Rep

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Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3-17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis. Aging is typically associated with impaired glucose tolerance, insulin resistance, and hepatosteatosis in both mice and humans. These metabolic disorders correlate with increased adiposity 1 , as well as an age-related decline in functional pancreatic β-cell mass (reviewed in 2). Identifying signals that modulate adipose tissue mass, glucose tolerance, insulin sensitivity, and/or functional β-cell mass in aging mammals could provide new targets for treatment of metabolic syndrome and diabetes. We previously showed that rGDF11 administration to aging mice results in a broad range of beneficial effects on brain 3,4 , skeletal muscle 5 , and cardiac tissues 6,7. GDF11 is a circulating blood factor which belongs to the larger transforming growth factor β (TGFβ) superfamily of extracellular ligands. New data published from multiple labs indicate that exogenous delivery of rGDF11 to rodent models of hyperglycemia (e.g. fed a high-fat diet HFD) reduced fasting blood glucose levels and improved glucose tolerance. The mechanism(s) behind these metabolic improvements may be due to a significant, yet transient, reduction in body mass 8-10. In fact, recent data suggests that rGDF11 stimulates secretion of adiponectin and a caloric restriction-like phenotype 10. On the other hand, others have shown that higher dosages of exogenous rGDF11 or viral overexpression of GDF11 via plasmid or viral vector caused cachexia, premature death, and anorexia 11-15. It is possible that these conflicting reports are due to drastically different doses and/or methodology used to artifically raise circulating GDF11 levels. Similarly, opposing results have also been reported regarding how GDF8, also known as myostatin, effects energy balance and metabolism 16-21. GDF8 is classically described as a potent negative regulator of skeletal muscle mass in addition to playin...

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“…To establish pressure overload‐induced cardiac pathological hypertrophy, male mice aged 10‐12 weeks weighing 22‐26 g were randomly assigned to either transverse aortic constriction (TAC) or sham surgery as described previously . Briefly, after anesthesia with 2% isoflurane, mice were intubated and mechanically ventilated.…”

Section: Methodsmentioning

confidence: 99%

Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling

Zhao

et al. 2019

Journal of Pineal Research

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Exercise-induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease-induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming-induced physiological hypertrophy and pressure overload-induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid-related orphan nuclear receptor-α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming-induced physiological hypertrophic murine hearts. In vivo and in vitro loss-of-function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti-hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese-dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro-hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti-hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti-hypertrophic effect on pathological but not physiological cardiac 2 of 21 | XU et al. 4 of 21 | XU et al.

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GDF11 Decreases Pressure Overload–Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death

Cited by 43 publications

References 49 publications

Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus

Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice

Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling

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