129 results on '"Murach, Kevin"'
Search Results
102. Commentaries on Viewpoint: Resistance training and exercise tolerance during high-intensity exercise: moving beyond just running economy and muscle strength.
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Bertuzzi, Romulo, Gáspari, Arthur F., Trojbicz, Lucas R., Silva-Cavalcante, Marcos D., Lima-Silva, Adriano E., Billaut, François, Girard, Oliver, Millet, Grégoire P., Bossi, Henrique, Hopker, James, Pandeló Jr., Domingos R., Fulton, Timothy J., Paris, Hunter L., Chapman, Robert F., Grosicki, Gregory J., Murach, Kevin A., Hureau, Thomas J., Dufour, Stéphane P., Favret, Fabrice, and Kruse, Nicholas T.
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- 2018
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103. MyoVision: software for automated high-content analysis of skeletal muscle immunohistochemistry.
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Yuan Wen, Murach, Kevin A., Vechetti Jr., Ivan J., Fry, hristopher S., Vickery, Chase, Peterson, Charlotte A., McCarthy, John J., and Campbell, Kenneth S.
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SKELETAL muscle ,IMMUNOHISTOCHEMISTRY ,FLUORESCENCE microscopy - Abstract
Analysis of skeletal muscle cross sections is an important experimental technique in muscle biology. Many aspects of immunohistochemistry and fluorescence microscopy can now be automated, but most image quantification techniques still require extensive human input, slowing progress and introducing the possibility of user bias. MyoVision is a new software package that was developed to overcome these limitations. The software improves upon previously reported automatic techniques and analyzes images without requiring significant human input and correction. When compared with data derived by manual quantification, MyoVision achieves an accuracy of ≥94% for basic measurements such as fiber number, fiber type distribution, fiber cross-sectional area, and myonuclear number. Scientists can download the software free from www.MyoVision.org and use it to automate the analysis of their own experimental data. This will improve the efficiency and consistency of the analysis of muscle cross sections and help to reduce the burden of routine image quantification in muscle biology. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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104. Less Is More: The Physiological Basis for Tapering in Endurance, Strength, and Power Athletes
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Murach, Kevin, primary and Bagley, James, additional
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- 2015
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105. Single Muscle Fiber Characteristics of The Oldest-Old
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Grosicki, Gregory, primary, Standley, Robert, additional, Murach, Kevin, additional, Raue, Ulrika, additional, Minchev, Kiril, additional, Coen, Paul, additional, Newman, Anne, additional, Cummings, Steven, additional, Harris, Tamara, additional, Kritchevsky, Stephen, additional, Goodpaster, Bret, additional, and Trappe, Scott, additional
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- 2015
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106. Skeletal muscle architectural adaptations to marathon run training
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Murach, Kevin, primary, Greever, Cory, additional, and Luden, Nicholas D., additional
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- 2015
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107. Improved single muscle fiber quality in the oldest-old.
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Grosicki, Greg J., Standley, Robert A., Murach, Kevin A., Raue, Ulrika, Minchev, Kiril, Coen, Paul M., Newman, Anne B., Cummings, Steven, Harris, Tamara, Kritchevsky, Stephen, Goodpaster, Bret H., and Trappe, Scott
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OLD-old ,SKELETAL muscle ,IMMUNOGLOBULIN heavy chains ,MYOSIN ,SODIUM dodecyl sulfate - Abstract
We examined single muscle fiber contractile function of the oldest-old (3F/2M, 89 ± 1 yr old) enrolled in The Health, Aging, and Body Composition Study (The Health ABC Study). Vastus lateralis muscle biopsies were obtained and single muscle fiber function was determined (n = 105) prior to myosin heavy chain (MHC) isoform identification with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cross-sectional area of MHC I muscle fibers (5,576 ± 333 μm
2 ; n = 58) was 21% larger (P < 0.05) than MHC IIa fibers (4,518 ± 386 μm2 ; n = 47). Normalized power (an indicator of muscle fiber quality incorporating size, strength, and speed) of MHC I and IIa muscle fibers was 2.3 ± 0.1 and 17.4 ± 0.8 W/l, respectively. Compared with previous research from our lab using identical procedures, MHC I normalized power was 28% higher than healthy 20 yr olds and similar to younger octogenarians (∼80 yr old). Normalized power of MHC IIa fibers was 63% greater than 20 yr olds and 39% greater than younger octogenarians. These comparative data suggest that power output per unit size (i.e., muscle quality) of remaining muscle fibers improves with age, a phenomenon more pronounced in MHC IIa fibers. Age-related single muscle fiber quality improvements may be a compensatory mechanism to help offset decrements in whole muscle function. [ABSTRACT FROM AUTHOR]- Published
- 2016
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108. Single Muscle Fiber Gene Expression with Run Taper
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Murach, Kevin, primary, Raue, Ulrika, additional, Wilkerson, Brittany, additional, Minchev, Kiril, additional, Jemiolo, Bozena, additional, Bagley, James, additional, Luden, Nicholas, additional, and Trappe, Scott, additional
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- 2014
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109. Is Long Duration Aerobic Exercise Necessary for Anaerobic Athletes?
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Murach, Kevin A., primary, Bagley, James R., additional, and Pfeiffer, Charles J., additional
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- 2013
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110. Concurrent aerobic exercise interferes with the satellite cell response to acute resistance exercise
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Babcock, Lyle, primary, Escano, Matthew, additional, D'Lugos, Andrew, additional, Todd, Kent, additional, Murach, Kevin, additional, and Luden, Nicholas, additional
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- 2012
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111. Methylome–proteome integration after late‐life voluntary exercise training reveals regulation and target information for improved skeletal muscle health.
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Chambers, Toby L., Dimet‐Wiley, Andrea, Keeble, Alexander R., Haghani, Amin, Lo, Wen‐Juo, Kang, Gyumin, Brooke, Robert, Horvath, Steve, Fry, Christopher S., Watowich, Stanley J., Wen, Yuan, and Murach, Kevin A.
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MUSCULAR hypertrophy , *SKELETAL muscle , *EXERCISE therapy , *UBIQUITIN ligases , *EXERCISE physiology , *MUSCLE fatigue - Abstract
Key points Exercise is a potent stimulus for combatting skeletal muscle ageing. To study the effects of exercise on muscle in a preclinical setting, we developed a combined endurance–resistance training stimulus for mice called progressive weighted wheel running (PoWeR). PoWeR improves molecular, biochemical, cellular and functional characteristics of skeletal muscle and promotes aspects of partial epigenetic reprogramming when performed late in life (22–24 months of age). In this investigation, we leveraged pan‐mammalian DNA methylome arrays and tandem mass‐spectrometry proteomics in skeletal muscle to provide detailed information on late‐life PoWeR adaptations in female mice relative to age‐matched sedentary controls (
n = 7–10 per group). Differential CpG methylation at conserved promoter sites was related to transcriptional regulation genes as well asNr4a3 ,Hes1 andHox genes after PoWeR. Using a holistic method of ‐omics integration called binding and expression target analysis (BETA), methylome changes were associated with upregulated proteins related to global and mitochondrial translation after PoWeR (P = 0.03). Specifically, BETA implicated methylation control of ribosomal, mitoribosomal, and mitochondrial complex I protein abundance after training. DNA methylation may also influence LACTB, MIB1 and UBR4 protein induction with exercise – all are mechanistically linked to muscle health. Computational cistrome analysis predicted several transcription factors including MYC as regulators of the exercise trained methylome–proteome landscape, corroborating prior late‐life PoWeR transcriptome data. Correlating the proteome to muscle mass and fatigue resistance revealed positive relationships with VPS13A and NPL levels, respectively. Our findings expose differential epigenetic and proteomic adaptations associated with translational regulation after PoWeR that could influence skeletal muscle mass and function in aged mice. Late‐life combined endurance–resistance exercise training from 22–24 months of age in mice is shown to improve molecular, biochemical, cellular andin vivo functional characteristics of skeletal muscle and promote aspects of partial epigenetic reprogramming and epigenetic age mitigation. Integration of DNA CpG 36k methylation arrays using conserved sites (which also contain methylation ageing clock sites) with exploratory proteomics in skeletal muscle extends our prior work and reveals coordinated and widespread regulation of ribosomal, translation initiation, mitochondrial ribosomal (mitoribosomal) and complex I proteins after combined voluntary exercise training in a sizeable cohort of female mice (n = 7–10 per group and analysis). Multi‐omics integration predicted epigenetic regulation of serine β‐lactamase‐like protein (LACTB – linked to tumour resistance in muscle), mind bomb 1 (MIB1 – linked to satellite cell and type 2 fibre maintenance) and ubiquitin protein ligase E3 component N‐recognin 4 (UBR4 – linked to muscle protein quality control) after training. Computational cistrome analysis identified MYC as a regulator of the late‐life training proteome, in agreement with prior transcriptional analyses. Vacuolar protein sorting 13 homolog A (VPS13A) was positively correlated to muscle mass, and the glycoprotein/glycolipid associated sialylation enzymeN ‐acetylneuraminate pyruvate lyase (NPL) was associated toin vivo muscle fatigue resistance. [ABSTRACT FROM AUTHOR]- Published
- 2024
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112. Point/Counterpoint. Is Long Duration Aerobic Exercise Necessary for Anaerobic Athletes?
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Murach, Kevin A., Bagley, James R., and Pfeiffer Jr, Charles J.
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LONG DURATION AEROBIC EXERCISE HAS LONG BEEN A STAPLE OF TRAINING PROGRAMS FOR BOTH AEROBIC AND ANAEROBIC ATHLETES. WITHOUT QUESTION, THIS MODE OF TRAINING HAS THE POTENTIAL TO INDUCE NUMEROUS PHYSIOLOGICAL BENEFITS WHICH ENHANCE METABOLIC AND CARDIOVASCULAR PERFORMANCE. HOWEVER, MUCH DEBATE EXISTS OVER WHETHER OR NOT ANAEROBIC ATHLETES ARE ABLE TO ACHIEVE THESE SAME ADAPTATIONS THROUGH OTHER FORMS OF EXERCISE. THIS QUESTIONS THE NECESSITY OF LONG DURATION AEROBIC EXERCISE FOR THESE ATHLETES. THE FOLLOWING COLUMN WILL ARGUE FOR (PRO) AND AGAINST (CON) THE NEED FOR ANAEROBIC ATHLETES TO ENGAGE IN LONG DURATION AEROBIC EXERCISE. [ABSTRACT FROM AUTHOR]
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- 2013
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113. Delineating the effects of aerobic training versus aerobic capacity on satellite cell behaviour in humans.
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Murach, Kevin A.
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SATELLITE cells , *PHYSIOLOGICAL aspects of aerobic exercises , *FIBROSIS , *REGULATION of erythropoiesis , *ENDURANCE sports , *PHYSIOLOGY - Abstract
The article focuses on a study by A. Hoedt and colleagues, published in this journal, which aimed at analyzing the effects of aerobic training versus aerobic capacity on satellite cell (SC) behaviour. Topics discussed include role of satellite cells in health, diseases, exercise adaptation, ageing, and regulating fibrosis. The study showed increased satellite cell myogenic commitment through erythropoiesis-stimulating agent (ESA) and endurance training and increased SC density by ESA treatment.
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- 2016
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114. Characterizing a Novel Rodent Exercise Model to Explore the Permanency of Myonuclear Accretion During Muscle Adaptation: 3263 Board #132 June 2 9:30 AM - 11:00 AM.
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Dungan, Cory M., Murach, Kevin A., Vechetti, Ivan, McCarthy, John J., and Peterson, Charlotte A.
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SKELETAL muscle physiology , *CONFERENCES & conventions , *EXERCISE physiology , *HUMAN growth , *CARDIOVASCULAR fitness - Published
- 2018
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115. Skeletal muscle hypertrophy: cell growth is cell growth.
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Burke BI, Ismaeel A, von Walden F, Murach KA, and McCarthy JJ
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- Animals, Humans, Mice, Muscle, Skeletal growth & development, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Cell Proliferation physiology, Hypertrophy
- Abstract
Roberts et al. have provided an insightful counterpoint to our review article on the utility of the synergist ablation model. The purpose of this review is to provide some further dialogue regarding the strengths and weaknesses of the synergist ablation model. Specifically, we highlight that the robustness of the model overshadows surgical limitations. We also compare the transcriptomic responses to synergist ablation in mice and resistance exercise in humans to identify common pathways. We conclude that "cell growth is cell growth" and that the mechanisms available to cells to accumulate biomass and increase in size are similar across cell types and independent of the rate of growth.
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- 2024
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116. The rRNA epitranscriptome and myonuclear SNORD landscape in skeletal muscle fibers contributes to ribosome heterogeneity and is altered by a hypertrophic stimulus.
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Cui M, Jannig P, Halladjian M, Figueiredo VC, Wen Y, Vechetti IJ, Krogh N, Jude B, Edman S, Lanner J, McCarthy J, Murach KA, Sejersen T, Nielsen H, and von Walden F
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- Animals, Mice, Hypertrophy genetics, Male, Mice, Inbred C57BL, RNA Processing, Post-Transcriptional, Muscle, Skeletal metabolism, Epigenesis, Genetic, Ribosomes metabolism, Ribosomes genetics, RNA, Ribosomal genetics, RNA, Ribosomal metabolism, Muscle Fibers, Skeletal metabolism, RNA, Small Nucleolar genetics, RNA, Small Nucleolar metabolism, Transcriptome
- Abstract
In cell biology, ribosomal RNA (rRNA) 2' O -methyl (2'- O -Me) is the most prevalent posttranscriptional chemical modification contributing to ribosome heterogeneity. The modification involves a family of small nucleolar RNAs (snoRNAs) and is specified by box C/D snoRNAs (SNORDs). Given the importance of ribosome biogenesis for skeletal muscle growth, we asked if rRNA 2'- O -Me in nascent ribosomes synthesized in response to a growth stimulus is an unrecognized mode of ribosome heterogeneity in muscle. To determine the pattern and dynamics of 2'- O -Me rRNA, we used a sequencing-based profiling method called RiboMeth-seq (RMS). We applied this method to tissue-derived rRNA of skeletal muscle and rRNA specifically from the muscle fiber using an inducible myofiber-specific RiboTag mouse in sedentary and mechanically overloaded conditions. These analyses were complemented by myonuclear-specific small RNA sequencing to profile SNORDs and link the rRNA epitranscriptome to known regulatory elements generated within the muscle fiber. We demonstrate for the first time that mechanical overload of skeletal muscle 1 ) induces decreased 2'- O -Me at a subset of skeletal muscle rRNA and 2 ) alters the SNORD profile in isolated myonuclei. These findings point to a transient diversification of the ribosome pool via 2'- O -Me during growth and adaptation in skeletal muscle. These findings suggest changes in ribosome heterogeneity at the 2'- O -Me level during muscle hypertrophy and lay the foundation for studies investigating the functional implications of these newly identified "growth-induced" ribosomes. NEW & NOTEWORTHY Ribosomal RNAs (rRNAs) are posttranscriptionally modified by 2' O -methyl (2'- O -Me). This study applied RiboMeth-seq (RMS) to detect changes in 2'- O -Me levels during skeletal muscle hypertrophy, uncovering transient diversification of the ribosome pool in skeletal muscle fibers. This work implies a role for ribosome heterogeneity in skeletal muscle growth and adaptation.
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- 2024
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117. microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.
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Ismaeel A, Peck BD, Montgomery MM, Burke BI, Goh J, Kang G, Franco AB, Xia Q, Goljanek-Whysall K, McDonagh B, McLendon JM, Koopmans PJ, Jacko D, Schaaf K, Bloch W, Gehlert S, Wen Y, Murach KA, Peterson CA, Boudreau RL, Fisher-Wellman KH, and McCarthy JJ
- Abstract
MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.
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- 2024
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118. Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia.
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Delfinis LJ, Ogilvie LM, Khajehzadehshoushtar S, Gandhi S, Garibotti MC, Thuhan AK, Matuszewska K, Pereira M, Jones RG 3rd, Cheng AJ, Hawke TJ, Greene NP, Murach KA, Simpson JA, Petrik J, and Perry CGR
- Abstract
Objectives: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice., Methods: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ~45, ~75 and ~90 days after EOC injection., Results: Primary ovarian tumour sizes were progressively larger at each time point while robust metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling., Conclusion: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-metastatic weakness during EOC in addition to therapies targeting cachexia., Competing Interests: Conflict of Interest None declared.
- Published
- 2024
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119. 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.
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Edman S, Jones RG 3rd, Jannig PR, Fernandez-Gonzalo R, Norrbom J, Thomas NT, Khadgi S, Koopmans PJ, Morena F, Peterson CS, Scott LN, Greene NP, Figueiredo VC, Fry CS, Zhengye L, Lanner JT, Wen Y, Alkner B, Murach KA, and von Walden F
- Abstract
Molecular control of recovery after exercise in muscle is temporally dynamic. A time course of biopsies around resistance exercise (RE) combined with -omics is necessary to better comprehend the molecular contributions of skeletal muscle adaptation in humans. Vastus lateralis biopsies before and 30 minutes, 3-, 8-, and 24-hours after acute RE were collected. A time-point matched biopsy-only group was also included. RNA-sequencing defined the transcriptome while DNA methylomics and computational approaches complemented these data. The post-RE time course revealed: 1) DNA methylome responses at 30 minutes corresponded to upregulated genes at 3 hours, 2) a burst of translation- and transcription-initiation factor-coding transcripts occurred between 3 and 8 hours, 3) global gene expression peaked at 8 hours, 4) ribosome-related genes dominated the mRNA landscape between 8 and 24 hours, 5) methylation-regulated MYC was a highly influential transcription factor throughout the 24-hour recovery and played a primary role in ribosome-related mRNA levels between 8 and 24 hours. The influence of MYC in human muscle adaptation was strengthened by transcriptome information from acute MYC overexpression in mouse muscle. To test whether MYC was sufficient for hypertrophy, we generated a muscle fiber-specific doxycycline inducible model of pulsatile MYC induction. Periodic 48-hour pulses of MYC over 4 weeks resulted in higher muscle mass and fiber size in the soleus of adult female mice. Collectively, we present a temporally resolved resource for understanding molecular adaptations to RE in muscle and reveal MYC as a regulator of RE-induced mRNA levels and hypertrophy., Competing Interests: Conflict of Interest: YW is the founder of MyoAnalytics LLC. The authors have no other conflicts to declare.
- Published
- 2024
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120. Biological sex divergence in transcriptomic profiles during the onset of hindlimb unloading-induced atrophy.
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Tsitkanou S, Morena da Silva F, Cabrera AR, Schrems ER, Murach KA, Washington TA, Rosa-Caldwell ME, and Greene NP
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- Humans, Mice, Male, Female, Animals, Aged, Muscle, Skeletal metabolism, Muscular Atrophy pathology, Fibrosis, Hindlimb metabolism, Transcriptome, Hindlimb Suspension physiology
- Abstract
Disuse-induced muscle atrophy is a common clinical problem observed mainly in older adults, intensive care units patients, or astronauts. Previous studies presented biological sex divergence in progression of disuse-induced atrophy along with differential changes in molecular mechanisms possibly underlying muscle atrophy. The aim of this study was to perform transcriptomic profiling of male and female mice during the onset and progression of unloading disuse-induced atrophy. Male and female mice underwent hindlimb unloading (HU) for 24, 48, 72, and 168 h ( n = 8/group). Muscles were weighed for each cohort and gastrocnemius was used for RNA-sequencing analysis. Females exhibited muscle loss as early as 24 h of HU, whereas males after 168 h of HU. In males, pathways related to proteasome degradation were upregulated throughout 168 h of HU, whereas in females these pathways were upregulated up to 72 h of HU. Lcn2 , a gene contributing to regulation of myogenesis, was upregulated by 6.46- to 19.86-fold across all time points in females only. A reverse expression of Fosb , a gene related to muscle degeneration, was observed between males (4.27-fold up) and females (4.57-fold down) at 24-h HU. Mitochondrial pathways related to tricarboxylic acid (TCA) cycle were highly downregulated at 168 h of HU in males, whereas in females this downregulation was less pronounced. Collagen-related pathways were consistently downregulated throughout 168 h of HU only in females, suggesting a potential biological sex-specific protective mechanism against disuse-induced fibrosis. In conclusion, females may have protection against HU-induced skeletal muscle mitochondrial degeneration and fibrosis through transcriptional mechanisms, although they may be more vulnerable to HU-induced muscle wasting compared with males. NEW & NOTEWORTHY Herein, we have assessed the transcriptomic response across biological sexes during the onset and progression of unloading disuse-induced atrophy in mice. We have demonstrated an inverse expression of Fosb between males and females, as well as differentially timed patterns of expressing atrophy-related pathways between sexes that are concomitant to the accelerated atrophy in females. We also identified in females signs of mechanisms to combat disuse-induced mitochondrial degeneration and fibrosis.
- Published
- 2023
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121. The life and times of cellular senescence in skeletal muscle: friend or foe for homeostasis and adaptation?
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Dungan CM, Wells JM, and Murach KA
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- Phenotype, Homeostasis, Cellular Senescence genetics, Muscle, Skeletal physiology
- Abstract
A gradual decline in skeletal muscle mass and function is closely tied to increased mortality and disease risk during organismal aging. Exercise training is the most effective way to enhance muscle health, but the adaptive response to exercise as well as muscle repair potential is blunted in older individuals. Numerous mechanisms contribute to the loss of muscle mass and plasticity as aging progresses. An emerging body of recent evidence implicates an accumulation of senescent ("zombie") cells in muscle as a contributing factor to the aging phenotype. Senescent cells cannot divide but can release inflammatory factors and create an unfavorable environment for homeostasis and adaptation. On balance, some evidence indicates that cells with senescent characteristics can be beneficial for the muscle adaptive process, specifically at younger ages. Emerging evidence also suggests that multinuclear muscle fibers could become senescent. In this review, we summarize current literature on the prevalence of senescent cells in skeletal muscle and highlight the consequences of senescent cell removal on muscle mass, function, and adaptability. We examine key limitations in the field of senescence specifically in skeletal muscle and identify areas of research that require future investigation. NEW & NOTEWORTHY There is evidence to suggest that senescent "zombie" cells may or may not accrue in aging skeletal muscle. When muscle is perturbed regardless of age, senescent-like cells do appear, and the benefits of removing them could be age-dependent. More work is needed to determine the magnitude of accumulation and source of senescent cells in muscle. Regardless, pharmacological senolytic treatment of aged muscle is beneficial for adaptation.
- Published
- 2023
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122. MicroRNA control of the myogenic cell transcriptome and proteome: the role of miR-16.
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Lim S, Lee DE, Morena da Silva F, Koopmans PJ, Vechetti IJ Jr, von Walden F, Greene NP, and Murach KA
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- Cell Differentiation genetics, Muscle Development genetics, Muscle Fibers, Skeletal metabolism, Proteome genetics, Proteomics, Transcriptome genetics, Animals, Mice, MicroRNAs genetics, MicroRNAs 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.
- Published
- 2023
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123. A glitch in the matrix: the pivotal role for extracellular matrix remodeling during muscle hypertrophy.
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Brightwell CR, Latham CM, Thomas NT, Keeble AR, Murach KA, and Fry CS
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- Collagen metabolism, Humans, Hypertrophy metabolism, Muscle, Skeletal metabolism, Extracellular Matrix metabolism, Muscle Fibers, Skeletal metabolism
- Abstract
Multinuclear muscle fibers are the most voluminous cells in skeletal muscle and the primary drivers of growth in response to loading. Outside the muscle fiber, however, is a diversity of mononuclear cell types that reside in the extracellular matrix (ECM). These muscle-resident cells are exercise-responsive and produce the scaffolding for successful myofibrillar growth. Without proper remodeling and maintenance of this ECM scaffolding, the ability to mount an appropriate response to resistance training in adult muscles is severely hindered. Complex cellular choreography takes place in muscles following a loading stimulus. These interactions have been recently revealed by single-cell explorations into muscle adaptation with loading. The intricate ballet of ECM remodeling involves collagen production from fibrogenic cells and ECM modifying signals initiated by satellite cells, immune cells, and the muscle fibers themselves. The acellular collagen-rich ECM is also a mechanical signal-transducer and rich repository of growth factors that may directly influence muscle fiber hypertrophy once liberated. Collectively, high levels of collagen expression, deposition, and turnover characterize a well-trained muscle phenotype. The purpose of this review is to highlight the most recent evidence for how the ECM and its cellular components affect loading-induced muscle hypertrophy. We also address how the muscle fiber may directly take part in ECM remodeling, and whether ECM dynamics are rate limiting for muscle fiber growth.
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- 2022
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124. Epigenetic evidence for distinct contributions of resident and acquired myonuclei during long-term exercise adaptation using timed in vivo myonuclear labeling.
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Murach KA, Dungan CM, von Walden F, and Wen Y
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- Animals, Cell Nucleus chemistry, Green Fluorescent Proteins analysis, Green Fluorescent Proteins metabolism, Male, Mice, Mice, Transgenic, Muscle Fibers, Skeletal chemistry, Physical Conditioning, Animal methods, Satellite Cells, Skeletal Muscle chemistry, Satellite Cells, Skeletal Muscle metabolism, Time Factors, Adaptation, Physiological physiology, Cell Nucleus metabolism, Epigenesis, Genetic physiology, Muscle Fibers, Skeletal metabolism, Physical Conditioning, Animal physiology, Staining and Labeling methods
- Abstract
Muscle fibers are syncytial postmitotic cells that can acquire exogenous nuclei from resident muscle stem cells, called satellite cells. Myonuclei are added to muscle fibers by satellite cells during conditions such as load-induced hypertrophy. It is difficult to dissect the molecular contributions of resident versus satellite cell-derived myonuclei during adaptation due to the complexity of labeling distinct nuclear populations in multinuclear cells without label transference between nuclei. To sidestep this barrier, we used a genetic mouse model where myonuclear DNA can be specifically and stably labeled via nonconstitutive H2B-GFP at any point in the lifespan. Resident myonuclei (Mn) were GFP-tagged in vivo before 8 wk of progressive weighted wheel running (PoWeR) in adult mice (>4-mo-old). Resident + satellite cell-derived myonuclei (Mn+SC Mn) were labeled at the end of PoWeR in a separate cohort. Following myonuclear isolation, promoter DNA methylation profiles acquired with low-input reduced representation bisulfite sequencing (RRBS) were compared to deduce epigenetic contributions of satellite cell-derived myonuclei during adaptation. Resident myonuclear DNA has hypomethylated promoters in genes related to protein turnover, whereas the addition of satellite cell-derived myonuclei shifts myonuclear methylation profiles to favor transcription factor regulation and cell-cell signaling. By comparing myonucleus-specific methylation profiling to previously published single-nucleus transcriptional analysis in the absence (Mn) versus the presence of satellite cells (Mn+SC Mn) with PoWeR, we provide evidence that satellite cell-derived myonuclei may preferentially supply specific ribosomal proteins to growing myofibers and retain an epigenetic "memory" of prior stem cell identity. These data offer insights on distinct epigenetic myonuclear characteristics and contributions during adult muscle growth.
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- 2022
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125. Depletion of resident muscle stem cells negatively impacts running volume, physical function, and muscle fiber hypertrophy in response to lifelong physical activity.
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Englund DA, Murach KA, Dungan CM, Figueiredo VC, Vechetti IJ Jr, Dupont-Versteegden EE, McCarthy JJ, and Peterson CA
- Subjects
- Adaptation, Physiological, Animals, Diphtheria Toxin genetics, Female, Gene Expression Regulation, Glycolysis, Hypertrophy, Mice, Transgenic, Muscle Fibers, Skeletal metabolism, Oxidation-Reduction, PAX7 Transcription Factor genetics, Peptide Fragments genetics, RNA, Untranslated genetics, Satellite Cells, Skeletal Muscle metabolism, Time Factors, Muscle Fibers, Skeletal pathology, Physical Conditioning, Animal, Running, Satellite Cells, Skeletal Muscle pathology, Sedentary Behavior
- Abstract
To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a nontranslational stimulus and/or have been performed over a relatively short time frame. Although it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long-term physical activity. The current study was designed to determine whether reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-diphtheria toxin A (DTA) mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 mo. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume, and the size of muscle proprioceptors (spindle fibers). Furthermore, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of G protein-coupled receptor (GPCR) signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long-term physical activity. These findings suggest that satellite cells play a role in preserving physical function during aging and influence muscle adaptation during sustained periods of physical activity.
- Published
- 2020
- Full Text
- View/download PDF
126. Resident muscle stem cells are not required for testosterone-induced skeletal muscle hypertrophy.
- Author
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Englund DA, Peck BD, Murach KA, Neal AC, Caldwell HA, McCarthy JJ, Peterson CA, and Dupont-Versteegden EE
- Subjects
- Animals, Disease Models, Animal, Hypertrophy chemically induced, Mice, Transgenic, Muscle Fibers, Skeletal physiology, PAX7 Transcription Factor genetics, Satellite Cells, Skeletal Muscle physiology, Muscle Fibers, Skeletal drug effects, Satellite Cells, Skeletal Muscle drug effects, Stem Cells drug effects, Testosterone pharmacology
- Abstract
It is postulated that testosterone-induced skeletal muscle hypertrophy is driven by myonuclear accretion as the result of satellite cell fusion. To directly test this hypothesis, we utilized the Pax7-DTA mouse model to deplete satellite cells in skeletal muscle followed by testosterone administration. Pax7-DTA mice (6 mo of age) were treated for 5 days with either vehicle [satellite cell replete (SC+)] or tamoxifen [satellite cell depleted (SC-)]. Following a washout period, a testosterone propionate or sham pellet was implanted for 21 days. Testosterone administration caused a significant increase in muscle fiber cross-sectional area in SC+ and SC- mice in both oxidative (soleus) and glycolytic (plantaris and extensor digitorum longus) muscles. In SC+ mice treated with testosterone, there was a significant increase in both satellite cell abundance and myonuclei that was completely absent in testosterone-treated SC- mice. These findings provide direct evidence that testosterone-induced muscle fiber hypertrophy does not require an increase in satellite cell abundance or myonuclear accretion.Listen to a podcast about this Rapid Report with senior author E. E. Dupont-Versteegden (https://ajpcell.podbean.com/e/podcast-on-paper-that-shows-testosterone-induced-skeletal-muscle-hypertrophy-does-not-need-muscle-stem-cells/).
- Published
- 2019
- Full Text
- View/download PDF
127. Elevated myonuclear density during skeletal muscle hypertrophy in response to training is reversed during detraining.
- Author
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Dungan CM, Murach KA, Frick KK, Jones SR, Crow SE, Englund DA, Vechetti IJ Jr, Figueiredo VC, Levitan BM, Satin J, McCarthy JJ, and Peterson CA
- Subjects
- Animals, Female, Hypertrophy pathology, Mice, Mice, Inbred C57BL, Muscle Fibers, Skeletal pathology, Muscle Fibers, Skeletal physiology, Physical Conditioning, Animal methods, Physical Conditioning, Animal physiology, Weight-Bearing physiology
- Abstract
Myonuclei gained during exercise-induced skeletal muscle hypertrophy may be long-lasting and could facilitate future muscle adaptability after deconditioning, a concept colloquially termed "muscle memory." The evidence for this is limited, mostly due to the lack of a murine exercise-training paradigm that is nonsurgical and reversible. To address this limitation, we developed a novel progressive weighted-wheel-running (PoWeR) model of murine exercise training to test whether myonuclei gained during exercise persist after detraining. We hypothesized that myonuclei acquired during training-induced hypertrophy would remain following loss of muscle mass with detraining. Singly housed female C57BL/6J mice performed 8 wk of PoWeR, while another group performed 8 wk of PoWeR followed by 12 wk of detraining. Age-matched sedentary cage-dwelling mice served as untrained controls. Eight weeks of PoWeR yielded significant plantaris muscle fiber hypertrophy, a shift to a more oxidative phenotype, and greater myonuclear density than untrained mice. After 12 wk of detraining, the plantaris muscle returned to an untrained phenotype with fewer myonuclei. A finding of fewer myonuclei simultaneously with plantaris deconditioning argues against a muscle memory mechanism mediated by elevated myonuclear density in primarily fast-twitch muscle. PoWeR is a novel, practical, and easy-to-deploy approach for eliciting robust hypertrophy in mice, and our findings can inform future research on the mechanisms underlying skeletal muscle adaptive potential and muscle memory.
- Published
- 2019
- Full Text
- View/download PDF
128. To hypertrophy and beyond! Myostatin and its association to intermuscular adipose tissue with exercise and aging.
- Author
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Murach KA
- Subjects
- Adipose Tissue, Humans, Hypertrophy, Exercise, Myostatin
- Published
- 2018
- Full Text
- View/download PDF
129. Concurrent aerobic exercise interferes with the satellite cell response to acute resistance exercise.
- Author
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Babcock L, Escano M, D'Lugos A, Todd K, Murach K, and Luden N
- Subjects
- Exercise Test, Humans, Male, Myosin Heavy Chains metabolism, Resistance Training, Young Adult, Exercise physiology, Muscle Fibers, Skeletal physiology, Muscle, Skeletal physiology, Satellite Cells, Skeletal Muscle physiology
- Abstract
The addition of aerobic exercise (AE) to a resistance exercise (RE) program (concurrent exercise, CE) can interfere with maximum muscle fiber growth achieved with RE. Further, CE appears to markedly affect the growth of myosin heavy chain (MHC) I, but not MHC IIa fibers. The mechanism responsible for this "interference" is unclear. Satellite cell (SC) responsiveness to exercise appears to influence muscle adaptation but has not yet been examined following acute concurrent exercise. Thus, we assessed the fiber-type-specific SC response to RE, AE, and CE exercise. Eight college-aged males completed the following two exercise trials: the RE trial, which consisted of unilateral leg extensions and presses (4 sets ≥ 10 repetitions: 75% 1 repetition maximum, RM); and the AE/CE trial, which included an identical RE protocol with the opposite leg, immediately followed by subjects cycling for 90 min (60% W(max)). Muscle biopsies were obtained from the vastus lateralis before and 4 days after each session. Samples were cross-sectioned, stained with antibodies against NCAM, Ki-67, and MHC I, counterstained with DAPI, and analyzed for SC density (SC per fiber), SC activation, and fiber type. SC density increased to a greater extent following RE (38 ± 10%), compared with CE (-6 ± 8%). Similarly, MHC I muscle fiber SC density displayed a greater increase following RE (46 ± 14%), compared with AE (-7 ± 17%) and CE (-8 ± 8%). Our data indicate that the SC response to RE is blunted when immediately followed by AE, at least in MHC I muscle fibers, and possibly MHC II fibers. This suggests that the physiological environment evoked by AE might attenuate the eventual addition of myonuclei important for maximum muscle fiber growth and consequent force-producing capacity.
- Published
- 2012
- Full Text
- View/download PDF
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