was bundled into a van by friends sporting balaclavas
</a>A stag party in northern <a href="https://www.theguardian.com/world/italy" data-link-name="in body link" data-component="auto-linked-tag">Italy</a> ended with nine men being charged with “causing public alarm” after they pretended to be terrorists to stage a prank kidnapping of the groom.
Armed with pellet guns and wearing balaclavas and black helmets, the men, aged between 23 and 31, turned up at their friend’s home in Trofarello, a small town on the outskirts of Turin, gagged him and loaded him into the back of a van before speeding off.
But the stunt on Saturday did not quite go according to plan. The men were reportedly pretending to be Isis terrorists and police immediately descended on the town after being inundated with calls from worried neighbours.
Read more</a>An elderly man, watching the scene from his window, fainted.
Police checkpoints were set up across the area as a hunt was launched to find the “kidnappers” and their captive.
The van was found outside the home of one of the men. The groom, still inside, was unaware that it was all a joke, Torino Today reported.
Police seized the fake weapons, helmets, balaclavas and clothing emblazoned with references to Isis, while charging the men for triggering a panic.
our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.
Volume 15 - 2024 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fendo.2024.1404047">https://doi.org/10.3389/fendo.2024.1404047</a>
Introduction: Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions
the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated
in human skeletal muscle (SM-GDF15) is not totally understood
the association of both forms of GDF15 with parameters of muscle strength
metabolism and inflammation was investigated
Methods: the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies
of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI)
either young (&lt;40 years-old) or old (&gt;70 years-old)
Other parameters included in the analysis were Isometric Quadriceps Strength (IQS)
as well as circulating levels of Adiponectin
Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed
Results: c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI
while only in LLMI associated with increased levels of Resistin
in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels
but interestingly SM-GDF15 is lower in LLMI with respect to HS
a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA
LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15
Conclusion: our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength
it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15
which is likely linked to a healthy and active state
in particular on Western societies that are rapidly aging
and the fact that elderly population is continuously increasing
early diagnosis and treatment of sarcopenia are becoming fundamental
of intracellular pro-GDF15 protein in human skeletal muscle (SM-GDF15)
it is not clear whether SM-GDF15 expression is just a sign of muscle stress and reflects c-GDF15 levels
or rather it may play a detrimental or beneficial role trying to promote or counteract muscle wasting and weakness
in the present study we have analyzed the levels of c-GDF15 and SM-GDF15 in both healthy subjects with an active life-style and patients with lower limb mobility impairment and a sedentary life-style
We have found that in patients c-GDF15 level is higher while
SM-GDF15 level is lower compared to healthy subjects
c-GDF15 level is inversely correlated with muscle strength in both healthy subjects and patients
supporting its use as a biomarker of sarcopenia and muscle dysfunction
The subjects were recruited in the framework of the EU Project &#x201c;MYOAGE&#x201d;. The study protocol was approved by the Ethical Committee of Istituto Ortopedico Rizzoli, Bologna, Italy (ethical clearance no. 10823 issued on April 26, 2010). All subjects signed an informed consent before entering the study. For this study, ethical aspects for aging research were considered, as illustrated in <a href="#B33">33</a>
Height and weight were measured for each subject and BMI was calculated as weight in kilograms divided by the square of the height in meters (kg/m2)
Blood samples were collected in the morning after an overnight fasting
Plasma samples were obtained after a 15 minutes centrifugation at 2,000 g at 4&#xb0;C
then rapidly frozen and stored at -80&#xb0;C until the analysis was performed
IL6 and GDF15 concentrations were obtained using commercial ELISA kits (Quantikine R&amp;D Systems)
according to manufacturer&#x2019;s instructions
Circulating Perilipin 2 (c-PLIN2) was measured using the ELISA commercial kit Human ADRP ELISA (E-EL-H0278
according to the manufacturer&#x2019;s instructions
Each analyte was measured in duplicate for each sample
Plasma IL15 was analyzed using the Simple Plex Human IL-15 Cartridge (ProteinSimple/Bio-Techne) run on an Ella Automated Immunoassay System (ProteinSimple/Bio-Techne)
isometric quadriceps strength (IQS) was measured with a quadriceps chair (Forcelink B.V)
the subjects were positioned in an upright position
with straps to fix the hips to the chair and the ankle to the force transducer
Three trials were conducted to measure maximal voluntary contraction of the quadriceps
Each trial was separated by one minute of rest
The trial with the highest force output was taken for analyses
the IQS was measured in seated position using a Handifor dynamometer (TRACTEL S.A
patients were asked to perform three series of 10 contractions
progressively increasing the strength developed
The highest peak torque was withheld for analyses
ultrasound imaging of the Vastus lateralis (VL) was performed using a portable ultrasound (Mylab25
Esaote) with a 7&#x2013;10 MHz linear probe
Acquisition was performed by a trained examiner
Muscle thickness was calculated as the vertical distance between muscle superficial and deep aponeuroses
at an equidistant point from right and left borders of the sagittal image
a whole-body scan to detect total fat and lean mass was performed
The scan was performed using Dual-energy X-ray absorptiometry (DXA) (Hologic QDR 4500
Muscle biopsies were taken from VL muscle from 23 HS
during the operation at the site of surgical incision
All biopsies were immediately frozen in liquid nitrogen and then stored at -80&#xb0;C
Proteins were obtained by lysis of about 40mg of frozen tissue using TEAD buffer (Tris-HCl 20 mM pH= 7.5
DTT 1mM) with protease and phosphatase inhibitors (Sigma)
Homogenization was performed using a motor driven homogenizer and lysates obtained were then centrifuged at 25,000 g for 1h at 4&#xb0;C
10 &#x3bc;g of total proteins were separated on a polyacrylamide gel (4-15% Mini-PROTEAN&#xae; TGX&#x2122; Precast Protein Gels
Proteins were then transferred to a nitrocellulose membrane (Trans-Blot Transfer Medium
Bio-Rad) and then immunoblotted with anti-Mic-1/GDF15 (Cell Signaling) primary antibody
Anti-GAPDH primary antibody (Novus Bio) was used as housekeeping for normalization
Images acquisition was performed with ChemiDoc Imaging System (Bio-Rad)
Band densitometry analysis was performed with Fiji software
and Pearson correlation were used for normally distributed data whereas Mann-Whitney test was used for data that did not follow a normal distribution
SPSS 17.0 for Windows was used for analyses
P values &lt;0.05 were considered statistically significant
a Canonical Discriminant Analysis (CDA) was used to evaluate which of the variables involved in the PCA were able to best discriminate the 4 groups of subjects involved in the test (healthy young subjects
The CDA is a dimension-reduction technique
related to principal component analysis and canonical correlation
able to perform both univariate and multivariate 1-way analyses
Given a classification character and several interval variables
which are linear combinations of the original interval variables
receiver operating characteristics (ROC) curves were constructed to assess the cut-off levels and the discriminatory ability of the above-mentioned parameters in HS and LLMI
We have previously reported that the level of c-GDF15 in patients with lower limb mobility impairment (LLMI) is higher than that of healthy subjects (HS), and that in both LLMI and HS, older subjects have higher levels of c-GDF15 with respect to younger ones (<a href="#B14">14</a>). The analysis of c-GDF15 in the present study confirmed previous results, i.e. higher c-GDF15 levels in LLMI vs HS and in &gt;70yrs vs &lt;40yrs subjects (<a href="#hsm">Supplementary Figures&#xa0;1A&#x2013;C</a>)
These results indicate that actually GDF15 protein follows different concentration trends in plasma and skeletal muscle
no correlation between SM-GDF15 and c-GDF15 was observed (see below)
Figure&#xa0;1 Western blotting analysis of GDF15 in the skeletal muscle (SM-GDF15)
(A) Representative immunoblotting image of GDF15 and GAPDH in the skeletal muscle
(B) Relative protein expression of GDF15 in the SM from 23 healthy subjects (HS) and 16 patients with lower limb mobility impairment (LLMI)
(C) Relative protein expression of GDF15 in the SM from 10 HS &lt;40 years (&lt;40) and 13 HS &gt;70 years (&gt;70)
(D) Relative protein expression of GDF15 in the SM from 7 LLMI &lt;40 and 9 LLMI &gt;70
The quantification was performed using Fiji software and normalized to GAPDH expression
We then sought for correlations of c-GDF15 and SM-GDF15 with biochemical, anthropometric and functional parameters [age, BMI, Isometric Quadriceps Strength (IQS), Adiponectin, Leptin, Resistin, Insulin, IL6, IL15, c-PLIN2, IGF-1] related to inflammation, metabolism, body composition and muscle functionality. Mean values of the above-mentioned parameters, analyzed in HS and LLMI, are summarized in <a href="#T1">Table&#xa0;1</a>
Table&#xa0;1 Summary of biochemical and anthropometric parameters of HS and LLMI patients
When we considered all the subjects analyzed (LLMI+HS), a positive correlation of c-GDF15 with age, IL6 and Resistin and a negative correlation with IGF-1 were observed. As far as SM-GDF15, a positive correlation with Adiponectin and a negative correlation with Insulin were observed (<a href="#f2">Figures&#xa0;2A&#x2013;F</a>)
Figure&#xa0;2 Linear regression analysis of c-GDF15 with (A) age
and of SM-GDF15 with (E) Insulin and (F) Adiponectin
Pearson correlation coefficient (r) and p-value are shown
When we considered HS group only, a positive correlation of c-GDF15 with age, BMI and IL6 and a negative one with IQS, IQS/BMI and IGF-1 were observed. For this group, data on body composition were available. Interestingly, SM-GDF15 correlated with fat percentage and inversely with lean percentage (27.6% &#xb1; 1.3 and 70.4% &#xb1; 1.3 of HS body composition on average, respectively) (<a href="#T2">Table&#xa0;2</a>)
Table&#xa0;2 Pearson correlations of c-GDF15 and SM-GDF15 with the metabolic and inflammatory parameters in HS (r: Pearson correlation coefficient; p: p-value)
Table&#xa0;3 Pearson correlations of c-GDF15 and SM-GDF15 with the metabolic and inflammatory parameters in LLMI (r: Pearson correlation coefficient; p: p-value)
No correlation was observed with either c-PLIN2 (a marker of adiposity according to <a href="#B28">28</a>) or IL15 (a positive modulator of muscle growth, according to <a href="#B35">35</a>)
these data indicate that c-GDF15 is correlated with decreased muscle strength and increased inflammation and could thus represent a biomarker of poor muscle function
To better understand the diagnostic role and the possible link of c-GDF15 and SM-GDF15 with the other parameters analyzed
we performed a principal component analysis (PCA) and a canonical discriminant analysis (CDA)
Figure&#xa0;3 Principal component analysis (PCA) in HS and LLMI
(A) Loading plot of the PCA showing the different groups of parameters
(B) Score plot of the PCA showing the association of the different groups of subjects (&lt;40 years HS
&lt;40 years LLMI and &gt;70 years LLMI) with the parameters analyzed
Empty red circles are HS &lt;40 years; empty blue circles are HS &gt;70 years; filled red circles are LLMI &lt;40 years; filled blue circles are LLMI &gt;70 years; filled triangles are LLMI &gt;85 years
CDA showed that the parameters considered could discriminate the subjects into four groups (&lt;40yrs HS, &gt;70yrs HS, &lt;40yrs LLMI and &gt;70yrs LLMI). The canonical 1 accounted for 67.93% of separation and the canonical 2 for 21.17%. In particular, &gt;70yrs LLMI were well separated from all other groups, mainly because of c-GDF15 and Leptin expression levels (<a href="#f4">Figure&#xa0;4</a>)
Figure&#xa0;4 Canonical discriminant analysis (CDA) in HS and LLMI
&lt;40 LLMI and &gt;70 LLMI based on the parameters analyzed
Red circle: &lt;40 HS; green circle: &gt;70 HS; blue circle: &lt;40 LLMI; yellow circle: &gt;70 LLMI
These data indicate that these parameters can discriminate between LLMI and HS and
that c-GDF15 and SM-GDF15 levels seem to characterize LLMI and HS
Table&#xa0;4 ROC analysis of metabolic and inflammatory parameters in HS
Figure&#xa0;5 Receiver operating characteristic (ROC) analysis in HS and LLMI
(A) ROC curves of Adiponectin and SM-GDF15 in HS
(B) ROC curves of Insulin and c-GDF15 in LLMI
Table&#xa0;5 ROC analysis of metabolic and inflammatory parameters in LLMI patients
It has been reported that plasma levels of GDF15 are associated with low muscle function and sarcopenia (<a href="#B14">14</a>, <a href="#B41">41</a>&#x2013;<a href="#B45">45</a>)
it is not yet clear what is the role of SM-GDF15 in muscle function and whether the levels of c-GDF15 are linked to SM-GDF15
given that skeletal muscles constitute the largest body component
in this study we addressed the following questions: i
are the levels of SM-GDF15 correlated with those of c-GDF15
are the levels of SM-GDF15 correlated with muscle strength or other parameters related to inflammation or metabolism
is there any change with age in SM-GDF15 and its possible correlations with other parameters
is it possible to discriminate patients suffering of muscle disuse or sarcopenia from healthy controls
as well as young from elderly subjects taking advantage of these parameters
Figure&#xa0;6 Working hypothesis on the diagnostic roles of c-GDF15 and SM-GDF15
Higher levels of SM-GDF15 and lower levels of c-GDF15 are observed in healthy subjects with functional muscles
and are associated with reduced inflammation
higher muscle strength and higher Adiponectin levels
and are associated with increased inflammation
higher IL6 levels and lower IGF-1 levels and muscle strength
it can be hypothesized that GDF15 expression is induced in contracting myofibers
where an intense mitochondrial activity is present
inactive muscle may display a reduced GDF15 expression but
Further experiments are needed to formally prove this hypothesis
the level of c-GDF15 derives from the sum of all these contributions
reflecting the general health state of a subject rather than muscle health alone
To further support the idea that the diagnostic meaning of c-GDF15 and SM-GDF15 are different
CDA and ROC analysis clearly indicate that these two variables have an opposite direction and can help discriminating between HS and LLMI groups
c-GDF15 is the main factor for discriminating &gt;70yrs patients
while &lt;40yrs patients seem to be discriminated by other parameters including Insulin and IL6
SM-GDF15 seems to be associated with muscle activity and can help discriminating healthy
As a whole, these data suggest that c-GDF15 is associated with decreased muscle strength and mass and can be useful to identify patients with muscle function impairment/sarcopenia, in particular elderly ones (<a href="#f6">Figure&#xa0;6</a>)
the relatively low number of subjects that have been studied and the lack of measurement of some parameters
due to the tiny amount of biopsy material available
the post-hoc power analysis indicated that the sample numerosity was high enough to grant for trustable results
The exact role of GDF15 within the muscle fibers remains poorly elucidated and the present data seem apparently in contrast with the well-known pro-cachectic and catabolic role of GDF15
It is however to note that the conclusions of the majority of studies stem from experiments only considering c-GDF15
Whether the level of this intramuscular form of GDF15 has precise biologic/metabolic effects at muscle level or it is rather a mere marker of muscle activity needs to be better clarified with further studies
The raw data supporting the conclusions of this article will be made available by the authors
The studies involving humans were approved by the Ethical Committee of Istituto Ortopedico Rizzoli
The studies were conducted in accordance with the local legislation and institutional requirements
The participants provided their written informed consent to participate in this study
The author(s) declare financial support was received for the research
The work has been co-funded from Next Generation EU
in the context of the National Recovery and Resilience Plan
Investment PE8 &#x2013; Project Age-It: &#x201c;Ageing Well in an Ageing Society&#x201d; to SS
This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022]
The work was also co-funded from the Italian Ministry of University and Research (MUR) PRIN 2022
Project # 2022KS8T4N &#x201c;GDF15 as a key player and a potential target to tackle ageing and age-associated diseases: an in silico
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
The author(s) declared that they were an editorial board member of Frontiers
This had no impact on the peer review process and the final decision
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations
Any product that may be evaluated in this article
or claim that may be made by its manufacturer
is not guaranteed or endorsed by the publisher
The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fendo.2024.1404047/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fendo.2024.1404047/full#supplementary-material</a>
Supplementary Figure&#xa0;1 | ELISA analysis of c-GDF15 levels in healthy subjects (HS) and patients with lower limb mobility impairment (LLMI)
(B) c-GDF15 level in HS of &lt;40 years of age (&lt;40) compared to HS of &gt;70 years of age (&gt;70)
(C) c-GDF15 level in LLMI &lt;40 compared to LLMI &gt;70
Supplementary Figure&#xa0;2 | ELISA analysis of plasma IL6 levels in HS and LLMI
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Salvioli S and Conte M (2024) Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health
Received: 20 March 2024; Accepted: 29 April 2024;Published: 14 May 2024
Copyright &#xa9; 2024 Chiariello, Conte, Rossetti, Trofarello, Salvioli and Conte. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
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*Correspondence: Stefano Salvioli, <a id="encmail">c3RlZmFuby5zYWx2aW9saUB1bmliby5pdA==</a>
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Former MEGADETH bassist David Ellefson has added more dates to his "Bass Warrior" tour across Europe for spring 2025
The trek will feature Ellefson and his solo band performing select cuts from his well-known catalog of MEGADETH hits
solo material and other hard rock and metal favorites which inspired him during his 40-year music career
When the original "Bass Warrior" tour was first announced
Ellefson said in a statement: "I've approached my career as that of a musical warrior
I eagerly anticipate bringing these songs back to the stage
while sharing introspective and entertaining anecdotes about their creation
It's been a wild ride of low notes and high stakes."
Ellefson told Eonmusic about the "Bass Warrior" shows: "That's sort of an extension now of what I started a few years ago called 'Basstory'
going through the history of my career of songs that people know
I've done a little bit of storytelling of course
but I'm taking it over into some places that I haven't even been to in a while that are a little harder to get to with big bands
So this is a little smaller and nimble where I could go into more intimate venues
and it's intentionally designed to be that
I like it's that; you're very active with the people."
Note: Some shows are walk-up or e-mail-only, so check <a href="http://www.basswarriortour.com" target="_blank" rel="noopener">basswarriortour.com</a> for the latest updates on ticket details.
Ellefson was fired from MEGADETH more than three years ago after sexually tinged messages and explicit video footage involving the bassist were posted on Twitter.
David was in MEGADETH from the band's inception in 1983 to 2002, and again from 2010 until his latest exit.
In 2004, Ellefson filed an $18.5-million lawsuit against Mustaine, alleging the MEGADETH leader shortchanged him on profits and backed out of a deal to turn Megadeth Inc. over to him when the band broke up in 2002. The lawsuit was eventually dismissed and Ellefson rejoined MEGADETH in 2010.
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