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Article ; Online: Smyd1: Implications for novel approaches in rhabdomyosarcoma therapy.

Berkholz, Janine / Schmitt, Angelika / Fragasso, Annunziata / Schmid, Anna-Celina / Munz, Barbara

2023 Volume 434, Issue 2, Page(s) 113863

Abstract: Rhabdomyosarcoma (RMS), a tumor that consists of poorly differentiated skeletal muscle cells, is the most common soft-tissue sarcoma in children. Despite considerable progress within the last decades, therapeutic options are still limited, warranting the ...

Abstract	Rhabdomyosarcoma (RMS), a tumor that consists of poorly differentiated skeletal muscle cells, is the most common soft-tissue sarcoma in children. Despite considerable progress within the last decades, therapeutic options are still limited, warranting the need for novel approaches. Recent data suggest deregulation of the Smyd1 protein, a sumoylation target as well as H3K4me2/3 methyltransferase and transcriptional regulator in myogenesis, and its binding partner skNAC, in RMS cells. Here, we show that despite the fact that most RMS cells express at least low levels of Smyd1 and skNAC, failure to upregulate expression of these genes in reaction to differentiation-promoting signals can always be observed. While overexpression of the Smyd1 gene enhances many aspects of RMS cell differentiation and inhibits proliferation rate and metastatic potential of these cells, functional integrity of the putative Smyd1 sumoylation motif and its SET domain, the latter being crucial for HMT activity, appear to be prerequisites for most of these effects. Based on these findings, we explored the potential for novel RMS therapeutic strategies, employing small-molecule compounds to enhance Smyd1 activity. In particular, we tested manipulation of (a) Smyd1 sumoylation, (b) stability of H3K4me2/3 marks, and (c) calpain activity, with calpains being important targets of Smyd1 in myogenesis. We found that specifically the last strategy might represent a promising approach, given that suitable small-molecule compounds will be available for clinical use in the future.
MeSH term(s)	Child ; Humans ; Transcription Factors/metabolism ; DNA-Binding Proteins/metabolism ; Rhabdomyosarcoma/genetics ; Rhabdomyosarcoma/therapy ; Rhabdomyosarcoma/pathology ; Muscle Fibers, Skeletal/metabolism ; Cell Differentiation/genetics ; Cell Line, Tumor
Chemical Substances	Transcription Factors ; DNA-Binding Proteins
Language	English
Publishing date	2023-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2023.113863
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Article ; Online: Implementation and evaluation of an individualized physical exercise promotion program in people with manifested risk factors for multimorbidity (MultiPill-Exercise): a study protocol for a pragmatic randomized controlled trial.

Schweda, Simone / Müller, Gerhard / Munz, Barbara / Sudeck, Gorden / Martus, Peter / Dierkes, Katja / Krauss, Inga

BMC public health

2022 Volume 22, Issue 1, Page(s) 1174

Abstract: Background: Multimorbidity is a major problem in Europe, increasing the need for prevention and rehabilitation programs. In Germany no guidelines have been developed that focus on patients with multiple chronic non-communicable diseases (NCDs). Benefits ...

Abstract	Background: Multimorbidity is a major problem in Europe, increasing the need for prevention and rehabilitation programs. In Germany no guidelines have been developed that focus on patients with multiple chronic non-communicable diseases (NCDs). Benefits of physical activity (PA) and exercise in NCDs have been proven, but most interventions focus on single conditions. The evaluation of the effectiveness, efficiency and safety of PA programs in patients suffering from multiple NCDs and the feasibility of the implementation within the health care service remain open research questions. Methods: The multi-site randomized controlled pragmatic trial includes 320 sedentary subjects with at least two of the following NCDs, either manifested or in a pre-stage with evident risk factors: Cardio-vascular disease, Diabetes mellitus type 2, knee/ hip osteoarthritis and obesity. Participants will be recruited from general practitioners and medical specialists and randomized to standard care of a statutory health insurance or MultiPill-Exercise. Standard care includes a choice of one or a maximum of two 8- to 12-week health programs, including nutrition, exercise, relaxation or special disease management programs. MultiPill-Exercise is based on the bio-psycho-social health model, considering a person-oriented perspective in light of given individual characteristics and context factors. The 24-weeks intervention focuses on aerobic and strengthening exercises in line with the WHO PA recommendations. Psychological and pedagogical elements along with behavior change techniques are implemented to ease the initiation and maintenance of exercise participation and lifestyle change, including nutrition. Primary outcome will be short- and long-term PA measured with the European Health Interview Survey-Physical Activity Questionnaire (EHIS-PAQ). Secondly, the effectiveness of the program on generic, disease specific, economic, and exercise behavioral parameters, as well as program adherence and safety will be evaluated. Discussion: Results of this trial evaluate the PA intervention program in people with multiple NCDs in a real-life scenario. It will serve as a proof of concept with the opportunity of translation into routine practice. This approach, as a multi-site RCT with its rigorous methods and standardized operating procedures for the conduction of the intervention, will allow valid conclusions for the implementation of PA interventions in people with multimorbidity. Trial registration: The trial was registered at www.drks.de (ID: DRKS00025033 ) on 30th September 2021.
MeSH term(s)	Humans ; Exercise ; Exercise Therapy/methods ; Health Promotion ; Multimorbidity ; Noncommunicable Diseases/rehabilitation ; Osteoarthritis, Knee/therapy ; Risk Factors ; Pragmatic Clinical Trials as Topic
Language	English
Publishing date	2022-06-13
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041338-5
ISSN	1471-2458 ; 1471-2458
ISSN (online)	1471-2458
ISSN	1471-2458
DOI	10.1186/s12889-022-13400-9
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Article: Adipokines as Predictive Biomarkers for Training Adaptation in Subjects with Multimorbidity-A Hypothesis-Generating Study.

Maturana, Felipe Mattioni / Rolf, Rebecca / Schweda, Simone / Reimer, Max / Widmann, Manuel / Burgstahler, Christof / Nieß, Andreas M / Krauss, Inga / Munz, Barbara

Journal of clinical medicine

2023 Volume 12, Issue 13

Abstract: Background: Physical exercise exerts a positive effect on many chronic conditions, specifically lifestyle-related diseases such as overweight and obesity, type 2 diabetes mellitus (T2DM), cardiovascular conditions and osteoarthritis (OA). As a result of ...

Abstract	Background: Physical exercise exerts a positive effect on many chronic conditions, specifically lifestyle-related diseases such as overweight and obesity, type 2 diabetes mellitus (T2DM), cardiovascular conditions and osteoarthritis (OA). As a result of common risk factors, most of these patients present with multiple conditions. Exercise- and disease-related biomarkers, such as adipokines, are emerging tools in training supervision and regulation; however, their significance in subjects with multimorbidities is unknown. Subjects and methods: To address this issue, adipokines leptin, adiponectin and resistin were assessed in a cohort of subjects with multimorbidities (n = 39) presenting with at least two of the abovementioned conditions or relevant risk factors before and after a six-month exercise and lifestyle intervention program ('MultiPill-Exercise'), and correlated with training adaptation, namely changes in relative maximum oxygen uptake (V·O2max). Results: There was a significant negative correlation between baseline leptin concentrations and training effect for relative V·O2max (after three months: rho = -0.54, Conclusions: Leptin might be a suitable surrogate biomarker in the context of exercise-based lifestyle intervention programs in subjects with multimorbidity.
Language	English
Publishing date	2023-06-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12134376
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Article ; Online: Physical Exercise and Epigenetic Modifications in Skeletal Muscle.

Widmann, Manuel / Nieß, Andreas M / Munz, Barbara

Sports medicine (Auckland, N.Z.)

2019 Volume 49, Issue 4, Page(s) 509–523

Abstract: Physical activity and sports play major roles in the overall health status of humans. It is well known that regular exercise helps to lower the risk for a broad variety of health problems, such as cardiovascular disease, type 2 diabetes, and cancer. ... ...

Abstract	Physical activity and sports play major roles in the overall health status of humans. It is well known that regular exercise helps to lower the risk for a broad variety of health problems, such as cardiovascular disease, type 2 diabetes, and cancer. Being physically active induces a wide variety of molecular adaptations, for example fiber type switches or other metabolic alterations, in skeletal muscle tissue. These adaptations are based on exercise-induced changes to the skeletal muscle transcriptome. Understanding their nature is crucial to improve the development of exercise-based therapeutic strategies. Recent research indicates that specifically epigenetic mechanisms, i.e., pathways that induce changes in gene expression patterns without altering the DNA base sequence, might play a major role in controlling skeletal muscle transcriptional patterns. Epigenetic mechanisms include DNA and histone modifications, as well as expression of specific microRNAs. They can be modulated by environmental factors or external stimuli, such as exercise, and eventually induce specific and fine-tuned changes to the transcriptional response. In this review, we highlight current knowledge on epigenetic changes induced in exercising skeletal muscle, their target genes, and resulting phenotypic changes. In addition, we raise the question of whether epigenetic modifications might serve as markers for the design and management of optimized and individualized training protocols, as prognostic tools to predict training adaptation, or even as targets for the design of "exercise mimics".
MeSH term(s)	Adaptation, Physiological/genetics ; Age Factors ; Endurance Training ; Epigenesis, Genetic ; Exercise ; Gene Expression Regulation ; Histones ; Humans ; MicroRNAs/genetics ; Muscle, Skeletal/physiology ; Protein Processing, Post-Translational ; Resistance Training ; Transcriptome
Chemical Substances	Histones ; MicroRNAs
Language	English
Publishing date	2019-02-18
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	605911-9
ISSN	1179-2035 ; 0112-1642
ISSN (online)	1179-2035
ISSN	0112-1642
DOI	10.1007/s40279-019-01070-4
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Article ; Online: The ROS scavenger PDTC affects adaptation to treadmill running in mice: distinct effects on murine body mass, resting heart rate and skeletal muscle fiber type composition.

Röchner, Franziska / Schmitt, Angelika / Brändle, Anne-Lena / Fragasso, Annunziata / Munz, Barbara

The Journal of experimental biology

2021 Volume 224, Issue Pt 6

Abstract: Regular exercise induces a broad spectrum of adaptation reactions in a variety of tissues and organs. However, the respective mechanisms are incompletely understood. In the context of their analysis, animal model systems, specifically rodent treadmill ... ...

Abstract	Regular exercise induces a broad spectrum of adaptation reactions in a variety of tissues and organs. However, the respective mechanisms are incompletely understood. In the context of their analysis, animal model systems, specifically rodent treadmill running protocols, play an important role. However, few researchers have studied different aspects of adaptation, such as cardiorespiratory and skeletal muscle training effects, within one set of experiments. Here, we analyzed physiological adaptation to 10 weeks of regular, moderate-intensity, uphill treadmill running in mice, a widely used model for endurance exercise training. To study the effects of reactive oxygen species (ROS), which have been suggested to be major regulators of training adaptation, a subgroup of mice was treated with the ROS scavenger PDTC (pyrrolidine dithiocarbamate). We found that mass gain in mice that exercised under PDTC treatment lagged behind that of all other experimental groups. In addition, both exercise and PDTC significantly and additively decreased resting heart rate. Furthermore, there was a trend towards an enhanced proportion of type 2A skeletal muscle fibers and differential expression of metabolism-associated genes, indicating metabolic and functional adaptation of skeletal muscle fibers. By contrast, there were no effects on grip strength and relative mass of individual muscles, suggesting that our protocol of uphill running did not increase skeletal muscle hypertrophy and strength. Taken together, our data suggest that a standard protocol of moderate-intensity uphill running induces adaptation reactions at multiple levels, part of which might be modulated by ROS, but does not enhance skeletal muscle hypertrophy and force.
Language	English
Publishing date	2021-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218085-6
ISSN	1477-9145 ; 0022-0949
ISSN (online)	1477-9145
ISSN	0022-0949
DOI	10.1242/jeb.234237
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Zs.A 2629: Show issues

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Article ; Online: siRNA-mediated inhibition of skNAC and Smyd1 expression disrupts myofibril organization: Immunofluorescence and electron microscopy study in C2C12 cells.

Berkholz, Janine / Eberle, Regina / Boller, Klaus / Munz, Barbara

Micron (Oxford, England : 1993)

2018 Volume 108, Page(s) 6–10

Abstract: skNAC (skeletal and heart muscle-specific variant of nascent polypeptide-associated complex) and Smyd1 (SET and MYND domain-containing 1) form a protein dimer which is specific for striated muscle cells. Its function is largely unknown. On the one hand, ... ...

Abstract	skNAC (skeletal and heart muscle-specific variant of nascent polypeptide-associated complex) and Smyd1 (SET and MYND domain-containing 1) form a protein dimer which is specific for striated muscle cells. Its function is largely unknown. On the one hand, skNAC-Smyd1 appears to control transcriptional processes in the nucleus, on the other hand, specifically at later stages of myogenic differentiation, both proteins translocate to the sarcoplasm and at least Smyd1 specifically associates with sarcomeric structures and might control myofibrillogenesis and/or sarcomere architecture. Here, using immunofluorescence and electron microscopy, we analyzed sarcomere formation and myofibril organization after siRNA-mediated knockdown of skNAC or Smyd1 expression in murine C2C12 skeletal muscle cells. We found that inhibition of skNAC or Smyd1 expression indeed prevents myofibrillogenesis and sarcomere formation, leading to a disorganized array of myofilaments predominantly within the region immediately beneath the plasma membrane.
MeSH term(s)	Animals ; Cell Line ; DNA-Binding Proteins/biosynthesis ; DNA-Binding Proteins/genetics ; Fluorescent Antibody Technique ; Mice ; Microscopy, Electron ; Molecular Chaperones/biosynthesis ; Molecular Chaperones/genetics ; Muscle Development/genetics ; Muscle Proteins/biosynthesis ; Muscle Proteins/genetics ; Muscle, Striated/cytology ; Myofibrils/genetics ; Myofibrils/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Sarcomeres/genetics ; Sarcomeres/metabolism ; Transcription Factors/biosynthesis ; Transcription Factors/genetics
Chemical Substances	DNA-Binding Proteins ; Molecular Chaperones ; Muscle Proteins ; RNA, Small Interfering ; Smyd1 protein, mouse ; Transcription Factors ; nascent-polypeptide-associated complex
Language	English
Publishing date	2018-02-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207808-9
ISSN	1878-4291 ; 0047-7206 ; 0968-4328
ISSN (online)	1878-4291
ISSN	0047-7206 ; 0968-4328
DOI	10.1016/j.micron.2018.02.009
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Article ; Online: miRNAs as markers for the development of individualized training regimens: A pilot study.

Widmann, Manuel / Mattioni Maturana, Felipe / Burgstahler, Christof / Erz, Gunnar / Schellhorn, Philipp / Fragasso, Annunziata / Schmitt, Angelika / Nieß, Andreas M / Munz, Barbara

Physiological reports

2022 Volume 10, Issue 5, Page(s) e15217

Abstract: Small, non-coding RNAs (microRNAs) have been shown to regulate gene expression in response to exercise in various tissues and organs, thus possibly coordinating their adaptive response. Thus, it is likely that differential microRNA expression might be ... ...

Abstract	Small, non-coding RNAs (microRNAs) have been shown to regulate gene expression in response to exercise in various tissues and organs, thus possibly coordinating their adaptive response. Thus, it is likely that differential microRNA expression might be one of the factors that are responsible for different training responses of different individuals. Consequently, determining microRNA patterns might be a promising approach toward the development of individualized training strategies. However, little is known on (1) microRNA patterns and their regulation by different exercise regimens and (2) possible correlations between these patterns and individual training adaptation. Here, we present microarray data on skeletal muscle microRNA patterns in six young, female subjects before and after six weeks of either moderate-intensity continuous or high-intensity interval training on a bicycle ergometer. Our data show that n = 36 different microRNA species were regulated more than twofold in this cohort (n = 28 upregulated and n = 8 downregulated). In addition, we correlated baseline microRNA patterns with individual changes in VO
MeSH term(s)	Adaptation, Physiological ; Biomarkers/metabolism ; Exercise/physiology ; Female ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Muscle, Skeletal/metabolism ; Pilot Projects
Chemical Substances	Biomarkers ; MicroRNAs
Language	English
Publishing date	2022-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.15217
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Article ; Online: Proof of Concept of a 6-Month Person-Oriented Exercise Intervention 'MultiPill-Exercise' among Patients at Risk of or with Multiple Chronic Diseases: Results of a One-Group Pilot Trial.

Schweda, Simone / Munz, Barbara / Burgstahler, Christof / Niess, Andreas Michael / Roesel, Inka / Sudeck, Gorden / Krauss, Inga

International journal of environmental research and public health

2022 Volume 19, Issue 15

Abstract: Physical exercise has been shown to be effective in the treatment of non-communicable chronic diseases. However, patients with multiple chronic diseases (multimorbidity) have received little attention in health policy. This pilot trial served as a proof ... ...

Abstract	Physical exercise has been shown to be effective in the treatment of non-communicable chronic diseases. However, patients with multiple chronic diseases (multimorbidity) have received little attention in health policy. This pilot trial served as a proof of concept of a 6-months person-oriented exercise intervention for people at risk of or with diagnosed cardiovascular diseases, diabetes mellitus type 2, overweight and/or hip/knee osteoarthritis, regarding effects on health outcomes as well as adherence and safety. The intervention (‘MultiPill-Exercise’) was designed to promote physical exercise participation, considering an individual perspective by addressing personal and environmental factors. Outcomes were assessed at baseline (t0) and after three- (t3) and six-months (t6). The primary outcome was self-reported physical exercise participation in minutes/week comparing t3 and t6 vs. t0. Secondary outcomes included cardio-respiratory fitness (maximum oxygen uptake VO2peak during incremental cycling ergometry), isometric peak torque of knee extensors and flexors, health-related quality of life (Veterans Rand 12 with its subscales of perceived general health (GH), mental health (MCS), and physical health (PCS)) and blood levels. Adherence to exercise (% of attended sessions during the first 12-weeks of the intervention) and adverse events were monitored as well. Data were analyzed using a non-parametric procedure for longitudinal data, estimating rank means (MRank) and relative treatment effects (RTE) as well as linear-mixed effect models for parametric data. The primary endpoint of physical exercise participation was significantly higher at t3 and t6 compared to baseline (t3 vs. t0: MRank = 77.1, p < 0.001, RTE: 0.66; t6 vs. t0: MRank = 70.6, p < 0.001, RTE = 0.60). Improvements at both follow-up time points compared to t0 were also found for relative VO2peak (t3 vs. t0 = 2.6 mL/kg/min, p < 0.001; t6 vs. t0 = 2.0 mL/kg/min, p = 0.001), strength of knee extensors (t3 vs. t0 = 11.7 Nm, p = 0.007; t6 vs. t0= 18.1 Nm, p < 0.001) and GH (t3 vs. t0 = 16.2, p = 0.003; t6 vs. t0 = 13.4, p = 0.008). No changes were found for MCS, PCS and for blood levels. Overall exercise adherence was 77%. No serious adverse events were recorded. Results of this pilot trial represent a first proof of concept for the intervention ‘MultiPill-Exercise’ that will now be implemented and evaluated in a real-world health care setting.
MeSH term(s)	Exercise Therapy/methods ; Humans ; Multiple Chronic Conditions ; Osteoarthritis, Hip/therapy ; Oxygen ; Oxygen Consumption ; Pilot Projects ; Quality of Life
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2022-08-02
Publishing country	Switzerland
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph19159469
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Article ; Online: Skeletal Muscle MicroRNA Patterns in Response to a Single Bout of Exercise in Females: Biomarkers for Subsequent Training Adaptation?

Grieb, Alexandra / Schmitt, Angelika / Fragasso, Annunziata / Widmann, Manuel / Mattioni Maturana, Felipe / Burgstahler, Christof / Erz, Gunnar / Schellhorn, Philipp / Nieß, Andreas M / Munz, Barbara

Biomolecules

2023 Volume 13, Issue 6

Abstract: microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females ( ...

Abstract	microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females (
MeSH term(s)	Humans ; Female ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Oxygen Consumption ; Oxygen/metabolism ; Exercise/physiology ; Muscle, Skeletal/metabolism ; Biomarkers/metabolism
Chemical Substances	MicroRNAs ; Oxygen (S88TT14065) ; Biomarkers
Language	English
Publishing date	2023-05-24
Publishing country	Switzerland
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13060884
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Article ; Online: Effects of the anti-oxidant PDTC in combination with a single bout of treadmill running on murine skeletal muscle.

Schmitt, Angelika / Brändle, Anne-Lena / Herzog, Pascal / Röchner, Franziska / Fragasso, Annunziata / Munz, Barbara

Redox report : communications in free radical research

2020 Volume 25, Issue 1, Page(s) 70–79

Abstract: Objectives: ...

Abstract	Objectives:
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Inflammation/metabolism ; Inflammation/pathology ; Inflammation/prevention & control ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/physiology ; Physical Conditioning, Animal ; Proline/analogs & derivatives ; Proline/pharmacology ; Thiocarbamates/pharmacology
Chemical Substances	Antioxidants ; Thiocarbamates ; prolinedithiocarbamate (135467-92-4) ; Proline (9DLQ4CIU6V)
Language	English
Publishing date	2020-08-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1305290-1
ISSN	1743-2928 ; 1351-0002
ISSN (online)	1743-2928
ISSN	1351-0002
DOI	10.1080/13510002.2020.1807088
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