Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies

Kalko, Susana G.; Paco, Sonia; Jou, Cristina; Rodríguez, Maria Angels; Meznarič, Marija; Rogac, Mihael; Jekovec-Vrhovsěk, Maja; Sciacco, Monica; Moggio, Maurizio; Fagiolari, Gigliola; Paepe, Boél De; Meırleır, Linda De; Ferrer, Isidre; Roig-Quilis, Manuel; Munell, Francina; Montoya, Julio; López‐Gallardo, Ester; Ruiz‐Pesini, Eduardo; Artuch, Rafael; Montero, Raquel; Torner, Ferrán; Nascimento, A.; Ortez, C.; Colomer, J.; Jiménez‐Mallebrera, Cecilia

doi:10.1186/1471-2164-15-91

Cited by 107 publications

(121 citation statements)

References 54 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…Moreover, we here confirm that muscle mitochondrial stress promotes the expression of Gdf15, encoding a cytokine of the TGF-b superfamily (also known as MIC-1/NAG-1). This is in line with a recent transcriptomic study on mitochondrial myopathy patients [65]. Notably, we here show that the induction of Gdf15 was not affected by the loss of FGF21 action.…”

Section: Discussionsupporting

confidence: 94%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

View full text Add to dashboard Cite

Objective: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood. Methods: We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21 À/À ) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions. Results: Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPR mt ) and amino acid biosynthetic pathways did not require the presence of FGF21.Conclusions: Here we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.

show abstract

Section: Discussionsupporting

confidence: 94%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

View full text Add to dashboard Cite

show abstract

“…So far, a few studies have found promising results regarding the diagnostic properties of GDF15 in patients with mitochondrial disease (Kalko et al 2014;Yatsuga 2014). None of these studies focused on the value of GDF15 as a surrogate marker for predicting or monitoring disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study reported growth and differentiation factor 15 (GDF15) as a potential new diagnostic biomarker for mitochondrial disease (Kalko et al 2014). GDF15 was already known as a quite nonspecific biomarker for cancer, as well as cardiac, pulmonary, renal, and gynecological disease (Izumiya et al 2014;Kempf and Wollert 2013;Trovik et al 2014;Yang et al 2014;Breit et al 2012;Montoro-Garcia et al 2012).…”

Section: Introductionmentioning

confidence: 99%

“…GDF15 was already known as a quite nonspecific biomarker for cancer, as well as cardiac, pulmonary, renal, and gynecological disease (Izumiya et al 2014;Kempf and Wollert 2013;Trovik et al 2014;Yang et al 2014;Breit et al 2012;Montoro-Garcia et al 2012). However, the concentrations reported in these disorders are within the 1.000-7.000 pg/ mL range (Dominguez-Rodriguez et al 2014;Ho et al 2013;Izumiya et al 2014;Montoro-Garcia et al 2012;Trovik et al 2014), whereas concentrations as high as 85.252 pg/mL were reported in patients with mitochondrial disease (Kalko et al 2014). A child with the m.3243A>G mutation, the most commonly observed mutation leading to mitochondrial disease, was reported to have a concentration of 6.999 pg/ mL (reference value, 380 pg/mL (95%CI, 59-701 pg/mL)).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Serum GDF15 Levels Correlate to Mitochondrial Disease Severity and Myocardial Strain, but Not to Disease Progression in Adult m.3243A>G Carriers

et al. 2015

View full text Add to dashboard Cite

In this observational cohort study, we examined the prognostic value of growth and differentiation factor 15 (GDF15) in indicating and monitoring general mitochondrial disease severity and progression in adult carriers of the m.3243A>G mutation.Ninety-seven adult carriers of the m.3243A>G mutation were included in this study. The Newcastle mitochondrial disease adult scale was used for rating mitochondrial disease severity. In parallel, blood was drawn for GDF15 analysis by ELISA. Forty-nine carriers were included in a follow-up study. In a small subset of subjects of whom an echocardiogram was available from general patient care, myocardial deformation was assessed using two-dimensional speckle-tracking strain analysis.A moderate positive correlation was found between the concentration of GDF15 and disease severity (r ¼ 0.59; p < 0.001). The concentration of serum GDF15 was higher in m.3243A>G carriers with diabetes mellitus, cardiomyopathy, and renal abnormalities. After a 2-year follow-up, no significant correlation was found between the change in disease severity and the change in the concentration of GDF15 or between the GDF15 level at the first assessment and the change in disease severity. In the subcohort of patients of whom an echocardiogram was available, the concentration of GDF15 correlated moderately to longitudinal global strain (r ¼ 0.55; p ¼ 0.006; n ¼ 23) but not to circumferential or radial strain.Our results indicate that serum GDF15 is not a strong surrogate marker for general mitochondrial disease severity. Its value in indicating myocardial deformation should be confirmed in a prospective longitudinal study.

show abstract

“…[16][17][18][19] Recently, it has been reported that GDF15 is secreted from skeletal muscle in response to mitochondrial stress. 20,21) Exploring the myokine associated with aging-related diseases may contribute to the extension of healthy lifespan. While TGFβ family may be involved in intertissue communication as myokines during aging, how the secretion of TGFβ family is regulated during skeletal muscle aging has not been clarified.…”

mentioning

confidence: 99%

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse

Ito

Nakanishi

Yamaji

et al. 2018

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

It has been identified that skeletal muscle is an endocrine tissue. Since skeletal muscle aging affects not only to muscle strength and function but to systemic aging and lifespan, myokines secreted from skeletal muscle may be crucial factors for intertissue communication during aging. In the present study, we investigated the expression of myokines associated with skeletal muscle aging in taurine transporter knockout (TauTKO) mice, which exhibit the accelerated skeletal muscle aging. Among transforming growth factor (TGF)-beta family genes, only growth and differentiation factor 15 (GDF15) was markedly higher (>3-fold) in skeletal muscle of old TauTKO mice compared with that of either young TauTKO mice or old wild-type mice. Circulating levels of GDF15 were also elevated in old TauTKO mice. An elevation in circulating GDF15 was also observed in very old (30-month-old) wild-type mice, while skeletal GDF15 levels were normal. The treatment of cultured mouse C2C12 myotubular cells with aging-related factors that mediate cellular stresses, such as oxidative stress (hydrogen peroxide) and endoplasmic reticulum stress (tunicamycin and thapsigargin), leads to an increase in GDF15 secretion. In conclusion, GDF15 is a myokine secreted by agingrelated stress and may control aging phenotype.Key words growth differentiation factor 15 (GDF15); sarcopenia; aging cell; skeletal muscle; myokine Aging-related loss of muscle mass and strength causes physical activities of daily living and decreases the QOL.1) Additionally, it has been demonstrated that skeletal muscle mass and strength are well associated with the mortality rate and aging-related diseases in human.2-4) Moreover, several studies in mammals and fruit flies demonstrated that stress-sensing in skeletal muscle influences systemic aging and lifespan, 4) suggesting that non-autonomous communication between aged skeletal muscle and whole body may play a key role in aging process. Skeletal muscle is an endocrine organ that produce cytokines and growth factors, which is called as myokines. 5)

show abstract

Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies

Cited by 107 publications

References 54 publications

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Serum GDF15 Levels Correlate to Mitochondrial Disease Severity and Myocardial Strain, but Not to Disease Progression in Adult m.3243A>G Carriers

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse

Contact Info

Product

Resources

About