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4. Circulating immune cell populations at rest and in response to acute endurance exercise in young adults with cerebral palsy.

Author

Kruse, Annika, Imery, Ian, Corell, Linnéa, Hjalmarsson, Emma, Fernandez‐Gonzalo, Rodrigo, Von Walden, Ferdinand, and Reitzner, Stefan M.

Subjects
YOUNG adults, CELL populations, CEREBRAL palsy, RATE of perceived exertion, IMMUNITY
Abstract

Aim: The aim of this observational study was to determine the immune status and function in young adults with cerebral palsy (CP) in comparison to typically developing individuals. Method: Blood samples from 12 individuals with CP (five males, seven females; mean age: 25 years 1 month (5 years 9 months); age range: 19–38 years) and 17 typically developing individuals (eight males, nine females; mean age: 31 years 4 months (6 years 2 months); age range: 20–40 years) were collected before, immediately after, and 1 hour after 45 minutes of frame running or running respectively. Independent t‐tests were used to compare heart rate, level of exertion, and baseline cell proportions between groups. Mixed model analysis of variance was utilized to investigate immune cell responses to exercise across groups. Results: Baseline levels of gamma delta (TCRγδ+) T‐cells were significantly higher (absolute percentage: +2.65, p = 0.028) in the individuals with CP. Several cell populations showed similar significant changes after exercise in both CP and typically developing groups. Cytotoxic (CD8+) T‐cells were only significantly elevated immediately after exercise in the typically developing participants (p < 0.01). Individuals with CP exhibited significantly lower heart rates (−11.1%, p < 0.01), despite similar ratings of perceived exertion. Interpretation: Elevated baseline TCRγδ+ T‐cells may indicate low‐grade inflammation in adults with CP. Although most of the cell populations showed typical responses to endurance exercise, the absence of response in CD8+ T‐cells in individuals with CP may indicate the need for higher intensity during exercise. What this paper adds: TCRγδ+ T‐cell baseline levels are elevated in adults with cerebral palsy (CP).The CD8+ T‐cell response to exercise was blunted in adults with CP.Exercise intensity is decisive for CD8+ T‐cell responses in individuals with CP. [ABSTRACT FROM AUTHOR]

Published
2024
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5. The 24-Hour Time Course of Integrated Molecular Responses to Resistance Exercise in Human Skeletal Muscle Implicates MYC as a Hypertrophic Regulator That is Sufficient for Growth

Author

Edman, Sebastian, primary, Jones, Ronald G., additional, Jannig, Paulo R., additional, Fernandez-Gonzalo, Rodrigo, additional, Norrbom, Jessica, additional, Thomas, Nicholas T., additional, Khadgi, Sabin, additional, Koopmans, Pieter Jan, additional, Morena, Francielly, additional, Peterson, Calvin S., additional, Scott, Logan N., additional, Greene, Nicholas P., additional, Figueiredo, Vandre C., additional, Fry, Christopher S., additional, Zhengye, Liu, additional, Lanner, Johanna T., additional, Wen, Yuan, additional, Alkner, Björn, additional, Murach, Kevin A., additional, and von Walden, Ferdinand, additional

Published
2024
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6. Exercise-Induced MYC as an Epigenetic Reprogramming Factor That Combats Skeletal Muscle Aging.

Author

Jones III, Ronald G., von Walden, Ferdinand, and Murach, Kevin A.

Abstract

Pulsatile Myc induction, through epigenetic alterations, mediates several aspects of the exercise response and may restore muscle plasticity with age. Of the "Yamanaka factors" Oct3/4 , Sox2 , Klf4 , and c-Myc (OSKM), the transcription factor c-Myc (Myc) is the most responsive to exercise in skeletal muscle and is enriched within the muscle fiber. We hypothesize that the pulsatile induction of MYC protein after bouts of exercise can serve to epigenetically reprogram skeletal muscle toward a more resilient and functional state. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Coordinated Regulation of Myonuclear DNA Methylation, mRNA, And miRNA Levels Associates with The Metabolic Response to Rapid Synergist Ablation-Induced Skeletal Muscle Hypertrophy in Female Mice

Author

Ismaeel, Ahmed, primary, Thomas, Nicholas T, additional, McCashland, Mariah, additional, Vechetti, Ivan J, additional, Edman, Sebastian, additional, Lanner, Johanna T, additional, Figueiredo, Vandré C, additional, Fry, Christopher S, additional, McCarthy, John J, additional, Wen, Yuan, additional, Murach, Kevin A, additional, and von Walden, Ferdinand, additional

Published
2023
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10. Coordinated Regulation of Myonuclear DNA Methylation, mRNA, and miRNA Levels Associates With the Metabolic Response to Rapid Synergist Ablation-Induced Skeletal Muscle Hypertrophy in Female Mice.

Author

Ismaeel, Ahmed, Thomas, Nicholas T, McCashland, Mariah, Vechetti, Ivan J, Edman, Sebastian, Lanner, Johanna T, Figueiredo, Vandré C, Fry, Christopher S, McCarthy, John J, Wen, Yuan, Murach, Kevin A, and von Walden, Ferdinand

Subjects
SKELETAL muscle, MOLECULAR biology, MUSCULAR hypertrophy, DNA methylation, DNA analysis, IMPRINTED polymers
Abstract

The central dogma of molecular biology dictates the general flow of molecular information from DNA that leads to a functional cellular outcome. In skeletal muscle fibers, the extent to which global myonuclear transcriptional alterations, accounting for epigenetic and post-transcriptional influences, contribute to an adaptive stress response is not clearly defined. In this investigation, we leveraged an integrated analysis of the myonucleus-specific DNA methylome and transcriptome, as well as myonuclear small RNA profiling to molecularly define the early phase of skeletal muscle fiber hypertrophy. The analysis of myonucleus-specific mature microRNA and other small RNA species provides new directions for exploring muscle adaptation and complemented the methylation and transcriptional information. Our integrated multi-omics interrogation revealed a coordinated myonuclear molecular landscape during muscle loading that coincides with an acute and rapid reduction of oxidative metabolism. This response may favor a biosynthesis-oriented metabolic program that supports rapid hypertrophic growth. Graphical Abstract [ABSTRACT FROM AUTHOR]

Published
2024
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24. MicroRNA control of the myogenic cell transcriptome and proteome: the role of miR-16.

Author

Seongkyun Lim, Lee, David E., Morena da Silva, Francielly, Koopmans, Pieter J., Vechetti Jr, Ivan J., von Walden, Ferdinand, Greene, Nicholas P., and Murach, Kevin A.

Subjects
MYOBLASTS, CYTOLOGY, PROGENITOR cells, TRANSCRIPTOMES, P53 antioncogene, PROTEOMICS, RNA metabolism
Abstract

MicroRNAs (miRs) control stem cell biology and fate. Ubiquitously expressed and conserved miR-16 was the first miR implicated in tumorigenesis. miR-16 is low in muscle during developmental hypertrophy and regeneration. It is enriched in proliferating myogenic progenitor cells but is repressed during differentiation. The induction of miR-16 blocks myoblast differentiation and myotube formation, whereas knockdown enhances these processes. Despite a central role for miR-16 in myogenic cell biology, how it mediates its potent effects is incompletely defined. In this investigation, global transcriptomic and proteomic analyses after miR-16 knockdown in proliferating C2C12 myoblasts revealed how miR-16 influences myogenic cell fate. Eighteen hours after miR-16 inhibition, ribosomal protein gene expression levels were higher relative to control myoblasts and p53 pathway-related gene abundance was lower. At the protein level at this same time point, miR-16 knockdown globally upregulated tricarboxylic acid (TCA) cycle proteins while downregulating RNA metabolism-related proteins. miR-16 inhibition induced specific proteins associated with myogenic differentiation such as ACTA2, EEF1A2, and OPA1. We extend prior work in hypertrophic muscle tissue and show that miR-16 is lower in mechanically overloaded muscle in vivo. Our data collectively point to how miR-16 is implicated in aspects of myogenic cell differentiation. A deeper understanding of the role of miR-16 in myogenic cells has consequences for muscle developmental growth, exercise-induced hypertrophy, and regenerative repair after injury, all of which involve myogenic progenitors. [ABSTRACT FROM AUTHOR]

Published
2023
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26. BioFACTS: biomarkers of rhabdomyolysis in the diagnosis of acute compartment syndrome – protocol for a prospective multinational, multicentre study involving patients with tibial fractures

Author

Nilsson, Abraham, primary, Ibounig, Thomas, additional, Lyth, Johan, additional, Alkner, Björn, additional, von Walden, Ferdinand, additional, Fornander, Lotta, additional, Rämö, Lasse, additional, Schmidt, Andrew, additional, and Schilcher, Jörg, additional

Published
2022
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27. Athlete-perceived impact of frame running on physical fitness, functional mobility and psychosocial outcomes

Author

Van der Linden, Marietta L, Van Schie, Petra E. M., Hjalmarsson, Emma, Andreopoulou, Georgia, Verheul, Martine H G, and Von Walden, Ferdinand

Subjects
para-sport, cerebral palsy, exercise, sports for people with disabilities, surveys and questionnaires, physical fitness, physical activity
Abstract

Objective: Frame Running (RaceRunning) allows people with moderate-to-severe mobility impairments to participate in physical activity using a 3-wheeled frame with a saddle and handlebars. The aim of this study was to investigate athlete-perceived impact of Frame Running on aspects of physical fitness, functional mobility and psychosocial outcomes.Design: Survey.Participants: Frame Running athletes aged 5 years and over.Methods: A survey was distributed to athletes through their club or sports organization.Results: The survey was completed by 115 athletes (53 females). Median age was 17 years (range 5-62 years) and 64 (57%) used a wheelchair or walker for distances over 50 m. Many felt that Frame Running stretched their muscles (n=93, 87%) and increased their self-confidence (n=63, 93%). Four (4%) reported extreme fatigue or sore muscles after training (n=17, 15%). Of the 110 athletes who had been participating in Frame Running for over 3 months, 46 (47%) reported being less out of breath during mobility tasks and 66 (66%) felt they had improved their functional mobility. However, 7 (7%) reported increased muscle tightness and 4 (4%) reported a Frame Running-related injury lasting more than 4 weeks.Conclusion: Frame Running is a safe physical activity with athlete-perceived benefits on physical fitness, functional mobility and psychosocial outcomes.

Published
2022

28. Extracellular vesicle characteristics and microRNA content in cerebral palsy and typically developed individuals at rest and in response to aerobic exercise

Author

Vechetti, Ivan J., Norrbom, Jessica, Alkner, Björn, Hjalmarsson, Emma, Palmcrantz, Alexandra, Pontén, Eva, Pingel, Jessica, von Walden, Ferdinand, and Fernandez-Gonzalo, Rodrigo

Subjects
exosomes, endurance exercise, miR-486, skeletal muscle, frame running, Idrottsvetenskap, Sport and Fitness Sciences
Abstract

In this study, the properties of circulating extracellular vesicles (EVs) were examined in cerebral palsy (CP) and typically developed (TD) individuals at rest and after aerobic exercise, focusing on the size, concentration, and microRNA cargo of EVs. Nine adult individuals with CP performed a single exercise bout consisting of 45 min of Frame Running, and TD participants completed either 45 min of cycling (n = 10; TD EX) or were enrolled as controls with no exercise (n = 10; TD CON). Blood was drawn before and 30 min after exercise and analyzed for EV concentration, size, and microRNA content. The size of EVs was similar in CP vs. TD, and exercise had no effect. Individuals with CP had an overall lower concentration (∼25%, p < 0.05) of EVs. At baseline, let-7a, let-7b and let-7e were downregulated in individuals with CP compared to TD (p < 0.05), while miR-100 expression was higher, and miR-877 and miR-4433 lower in CP compared to TD after exercise (p < 0.05). Interestingly, miR-486 was upregulated ∼2-fold in the EVs of CP vs. TD both at baseline and after exercise. We then performed an in silico analysis of miR-486 targets and identified the satellite cell stemness factor Pax7 as a target of miR-486. C2C12 myoblasts were cultured with a miR-486 mimetic and RNA-sequencing was performed. Gene enrichment analysis revealed that several genes involved in sarcomerogenesis and extracellular matrix (ECM) were downregulated. Our data suggest that circulating miR-486 transported by EVs is elevated in individuals with CP and that miR-486 alters the transcriptome of myoblasts affecting both ECM- and sarcomerogenesis-related genes, providing a link to the skeletal muscle alterations observed in individuals with CP In this study, the properties of circulating extracellular vesicles (EVs) were examined in cerebral palsy (CP) and typically developed (TD) individuals at rest and after aerobic exercise, focusing on the size, concentration, and microRNA cargo of EVs. Nine adult individuals with CP performed a single exercise bout consisting of 45 min of Frame Running, and TD participants completed either 45 min of cycling (n = 10; TD EX) or were enrolled as controls with no exercise (n = 10; TD CON). Blood was drawn before and 30 min after exercise and analyzed for EV concentration, size, and microRNA content. The size of EVs was similar in CP vs. TD, and exercise had no effect. Individuals with CP had an overall lower concentration (∼25%, p < 0.05) of EVs. At baseline, let-7a, let-7b and let-7e were downregulated in individuals with CP compared to TD (p < 0.05), while miR-100 expression was higher, and miR-877 and miR-4433 lower in CP compared to TD after exercise (p < 0.05). Interestingly, miR-486 was upregulated ∼2-fold in the EVs of CP vs. TD both at baseline and after exercise. We then performed an in silico analysis of miR-486 targets and identified the satellite cell stemness factor Pax7 as a target of miR-486. C2C12 myoblasts were cultured with a miR-486 mimetic and RNA-sequencing was performed. Gene enrichment analysis revealed that several genes involved in sarcomerogenesis and extracellular matrix (ECM) were downregulated. Our data suggest that circulating miR-486 transported by EVs is elevated in individuals with CP and that miR-486 alters the transcriptome of myoblasts affecting both ECM- and sarcomerogenesis-related genes, providing a link to the skeletal muscle alterations observed in individuals with CP.

Published
2022

31. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans

Author

von Walden, Ferdinand, primary, Fernandez-Gonzalo, Rodrigo, additional, Norrbom, Jessica, additional, Emanuelsson, Eric B., additional, Figueiredo, Vandré C., additional, Gidlund, Eva-Karin, additional, Norrbrand, Lena, additional, Liu, Chang, additional, Sandström, Philip, additional, Hansson, Björn, additional, Wan, Junxiang, additional, Cohen, Pinchas, additional, and Alkner, Björn, additional

Published
2021
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33. Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise

Author

Figueiredo, Vandré C., primary, Wen, Yuan, additional, Alkner, Björn, additional, Fernandez‐Gonzalo, Rodrigo, additional, Norrbom, Jessica, additional, Vechetti, Ivan J., additional, Valentino, Taylor, additional, Mobley, C. Brooks, additional, Zentner, Gabriel E., additional, Peterson, Charlotte A., additional, McCarthy, John J., additional, Murach, Kevin A., additional, and von Walden, Ferdinand, additional

Published
2021
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34. Mechanical overload‐induced muscle‐derived extracellular vesicles promote adipose tissue lipolysis

Author

Vechetti, Ivan J., primary, Peck, Bailey D., additional, Wen, Yuan, additional, Walton, R. Grace, additional, Valentino, Taylor R., additional, Alimov, Alexander P., additional, Dungan, Cory M., additional, Van Pelt, Douglas W., additional, von Walden, Ferdinand, additional, Alkner, Björn, additional, Peterson, Charlotte A., additional, and McCarthy, John J., additional

Published
2021
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36. Epigenetic Marks at the Ribosomal DNA Promoter in Skeletal Muscle Are Negatively Associated With Degree of Impairment in Cerebral Palsy

Author

von Walden, Ferdinand, Fernandez-Gonzalo, Rodrigo, Pingel, Jessica, McCarthy, John, Stål, Per, and Pontén, Eva

Subjects
cerebral palsy, DNA methylation, epigenetics, Pediatrics, Perinatology and Child Health, ribosome biogenesis, Pediatrik, Brief Research Report, skeletal muscle, Pediatrics
Abstract

Introduction: Cerebral palsy (CP) is the most common motor impairment in children. Skeletal muscles in individuals with CP are typically weak, thin, and stiff. Whether epigenetic changes at the ribosomal DNA (rDNA) promoter are involved in this dysregulation remains unknown. Methods: Skeletal muscle samples were collected from 19 children with CP and 10 typically developed (TD) control children. Methylation of the rDNA promoter was analyzed using the Agena Epityper Mass array and gene expression by qRT-PCR. Results: Biceps brachii muscle ribosome biogenesis was suppressed in CP as compared to TD. Average methylation of the rDNA promoter was not different between CP and TD but negatively correlated to elbow flexor contracture in the CP group. Discussions: We observed a negative correlation between rDNA promoter methylation and degree of muscle contracture in the CP group. Children with CP with more severe motor impairment had less methylation of the rDNA promoter compared to less affected children. This finding suggests the importance of neural input and voluntary muscle movements for promoter methylation to occur in the biceps muscle.

Published
2020

37. Genetic and Epigenetic Regulation of Skeletal Muscle Ribosome Biogenesis with Exercise

Author

Figueiredo, Vandré C., primary, Wen, Yuan, additional, Alkner, Björn, additional, Fernandez-Gonzalo, Rodrigo, additional, Norrbom, Jessica, additional, Vechetti, Ivan J., additional, Valentino, Taylor, additional, Mobley, C. Brooks, additional, Zentner, Gabriel E., additional, Peterson, Charlotte A., additional, McCarthy, John J., additional, Murach, Kevin A., additional, and von Walden, Ferdinand, additional

Published
2020
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46. Skeletal muscle signaling responses to resistance exercise of the elbow extensors are not compromised by a preceding bout of aerobic exercise

Author

Hansson, Björn, primary, Olsen, Luke A., additional, Nicoll, Justin X., additional, von Walden, Ferdinand, additional, Melin, Michael, additional, Strömberg, Anna, additional, Rullman, Eric, additional, Gustafsson, Thomas, additional, Fry, Andrew C., additional, Fernandez-Gonzalo, Rodrigo, additional, and Lundberg, Tommy R., additional

Published
2019
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48. Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease.

Author

Chang Liu, Gidlund, Eva-Karin, Witasp, Anna, Qureshi, Abdul Rashid, Söderberg, Magnus, Thorell, Anders, Nader, Gustavo A., Barany, Peter, Stenvinkel, Peter, and von Walden, Ferdinand

Subjects
SKELETAL muscle, CHRONIC kidney failure, PREMATURE aging (Medicine), GLOMERULAR filtration rate, MUSCLE proteins, OXIDATIVE stress
Abstract

Advanced chronic kidney disease (CKD) is characterized by a premature aging phenotype of multifactorial origin. Mitochondrial dysfunction is prevalent in CKD and has been proposed as a major contributor to poor muscle function. Although the mitochondria-derived peptides (MDPs) humanin and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis, and glucose control, the implications of MDP in CKD are unknown. We investigated humanin and MOTS-c protein expression in skeletal muscle and serum levels in CKD at stage 5 (glomerular filtration rate: < 15 ml/min) patients and age-matched controls with normal renal function. Whereas circulating levels of humanin were increased in CKD, local muscle expression was reduced. In contrast, MOTS-c levels were reduced in both skeletal muscle and serum in CKD. Humanin in serum correlated positively to circulating TNF levels. Reduced MDP levels in skeletal muscle were associated with lower mitochondrial density and evidence of oxidative stress. These results indicate a differential regulation of MDPs in CKD and suggest an alternative site for humanin production than skeletal muscle in the uremic milieu. MDP levels were linked to systemic inflammation and evidence of oxidative stress in the muscle, two hallmark features of premature aging and uremia. [ABSTRACT FROM AUTHOR]

Published
2019
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50. Muscle contractures in patients with cerebral palsy and acquired brain injury are associated with extracellular matrix expansion, pro‐inflammatory gene expression, and reduced rRNA synthesis

Author

Von Walden, Ferdinand, primary, Gantelius, Stefan, additional, Liu, Chang, additional, Borgström, Hanna, additional, Björk, Lars, additional, Gremark, Ola, additional, Stål, Per, additional, Nader, Gustavo A., additional, and PontéN, Eva, additional

Published
2018
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