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Article ; Online: Aging, Osteo-Sarcopenia, and Musculoskeletal Mechano-Transduction

Jenna M. Leser / Anicca Harriot / Heather V. Buck / Christopher W. Ward / Joseph P. Stains

Frontiers in Rehabilitation Sciences, Vol

2021 Volume 2

Abstract: The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, ... ...

Abstract	The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, falls, low-energy fractures, and increased risk of co-morbid disease that leads to musculoskeletal frailty. The biology of osteo-sarcopenia is most understood in the context of systemic neuro-endocrine and immune/inflammatory alterations that drive inflammation, oxidative stress, reduced autophagy, and cellular senescence in the bone and muscle. Here we integrate these concepts to our growing understanding of how bone and muscle senses, responds and adapts to mechanical load. We propose that age-related alterations in cytoskeletal mechanics alter load-sensing and mechano-transduction in bone osteocytes and muscle fibers which underscores osteo-sarcopenia. Lastly, we examine the evidence for exercise as an effective countermeasure to osteo-sarcopenia.
Keywords	bone ; muscle ; microtubules ; mechanotransduction ; sarcopenia ; cytoskeleton ; Other systems of medicine ; RZ201-999 ; Medical technology ; R855-855.5
Subject code	610
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: X-ROS Signaling Depends on Length-Dependent Calcium Buffering by Troponin

Sarita Limbu / Benjamin L. Prosser / William J. Lederer / Christopher W. Ward / Mohsin S. Jafri

Cells, Vol 10, Iss 1189, p

2021 Volume 1189

Abstract: The stretching of a cardiomyocyte leads to the increased production of reactive oxygen species that increases ryanodine receptor open probability through a process termed X-ROS signaling. The stretching of the myocyte also increases the calcium affinity ... ...

Abstract	The stretching of a cardiomyocyte leads to the increased production of reactive oxygen species that increases ryanodine receptor open probability through a process termed X-ROS signaling. The stretching of the myocyte also increases the calcium affinity of myofilament Troponin C, which increases its calcium buffering capacity. Here, an integrative experimental and modeling study is pursued to explain the interplay of length-dependent changes in calcium buffering by troponin and stretch-activated X-ROS calcium signaling. Using this combination, we show that the troponin C-dependent increase in myoplasmic calcium buffering during myocyte stretching largely offsets the X-ROS-dependent increase in calcium release from the sarcoplasmic reticulum. The combination of modeling and experiment are further informed by the elimination of length-dependent changes to troponin C calcium binding in the presence of blebbistatin. Here, the model suggests that it is the X-ROS signaling-dependent Ca 2+ release increase that serves to maintain free myoplasmic calcium concentrations during a change in myocyte length. Together, our experimental and modeling approaches have further defined the relative contributions of X-ROS signaling and the length-dependent calcium buffering by troponin in shaping the myoplasmic calcium transient.
Keywords	heart ; reactive oxygen species ; calcium ; blebbistatin ; computational model ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Depletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy

Justin G. Boyer / Jiuzhou Huo / Sarah Han / Julian R. Havens / Vikram Prasad / Brian L. Lin / David A. Kass / Taejeong Song / Sakthivel Sadayappan / Ramzi J. Khairallah / Christopher W. Ward / Jeffery D. Molkentin

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 10

Abstract: Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue ... ...

Abstract	Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue wasting in the muscular dystrophies.
Keywords	Science ; Q
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy

Brian L. Lin / Joseph Y. Shin / William P.D. Jeffreys / Nadan Wang / Clarisse A. Lukban / Megan C. Moorer / Esteban Velarde / Olivia A. Hanselman / Seoyoung Kwon / Suraj Kannan / Ryan C. Riddle / Christopher W. Ward / Steven S. Pullen / Antonio Filareto / David A. Kass

JCI Insight, Vol 7, Iss

2022 Volume 19

Abstract: Gene mutations causing loss of dystrophin result in the severe muscle disease known as Duchenne muscular dystrophy (DMD). Despite efforts at genetic repair, DMD therapy remains largely palliative. Loss of dystrophin destabilizes the sarcolemmal membrane, ...

Abstract	Gene mutations causing loss of dystrophin result in the severe muscle disease known as Duchenne muscular dystrophy (DMD). Despite efforts at genetic repair, DMD therapy remains largely palliative. Loss of dystrophin destabilizes the sarcolemmal membrane, inducing mechanosensitive cation channels to increase calcium entry and promote cell damage and, eventually, muscle dysfunction. One putative channel is transient receptor potential canonical 6 (TRPC6); we have shown that TRPC6 contributed to abnormal force and calcium stress-responses in cardiomyocytes from mice lacking dystrophin that were haplodeficient for utrophin (mdx/utrn+/– [HET] mice). Here, we show in both the HET mouse and the far more severe homozygous mdx/utrn–/– mouse that TRPC6 gene deletion or its selective pharmacologic inhibition (by BI 749327) prolonged survival 2- to 3-fold, improving skeletal and cardiac muscle and bone defects. Gene pathways reduced by BI 749327 treatment most prominently regulated fat metabolism and TGF-β1 signaling. These results support the testing of TRPC6 inhibitors in human trials for other diseases as a novel DMD therapy.
Keywords	Cardiology ; Muscle biology ; Medicine ; R
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

Nicole R Gould / Katrina M Williams / Humberto C Joca / Olivia M Torre / James S Lyons / Jenna M Leser / Manasa P Srikanth / Marcus Hughes / Ramzi J Khairallah / Ricardo A Feldman / Christopher W Ward / Joseph P Stains

eLife, Vol

2021 Volume 10

Abstract: The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost ... ...

Abstract	The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minute-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically and hormonally activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.
Keywords	osteocyte ; sclerostin ; parathyroid hormone ; lysosome ; mechanical load ; bone ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: μ-Crystallin in Mouse Skeletal Muscle Promotes a Shift from Glycolytic toward Oxidative Metabolism

Christian J. Kinney / Andrea O'Neill / Kaila Noland / Weiliang Huang / Joaquin Muriel / Valeriy Lukyanenko / Maureen A. Kane / Christopher W. Ward / Alyssa F. Collier / Joseph A. Roche / John C. McLenithan / Patrick W. Reed / Robert J. Bloch

Current Research in Physiology, Vol 4, Iss , Pp 47-

2021 Volume 59

Abstract: μ-Crystallin, encoded by the CRYM gene, binds the thyroid hormones, T3 and T4. Because T3 and T4 are potent regulators of metabolism and gene expression, and CRYM levels in human skeletal muscle can vary widely, we investigated the effects of ... ...

Abstract	μ-Crystallin, encoded by the CRYM gene, binds the thyroid hormones, T3 and T4. Because T3 and T4 are potent regulators of metabolism and gene expression, and CRYM levels in human skeletal muscle can vary widely, we investigated the effects of overexpression of Crym. We generated transgenic mice, Crym tg, that expressed Crym protein specifically in skeletal muscle at levels 2.6–147.5 fold higher than in controls. Muscular functions, Ca2+ transients, contractile force, fatigue, running on treadmills or wheels, were not significantly altered, although T3 levels in tibialis anterior (TA) muscle were elevated ~190-fold and serum T4 was decreased 1.2-fold. Serum T3 and thyroid stimulating hormone (TSH) levels were unaffected. Crym transgenic mice studied in metabolic chambers showed a significant decrease in the respiratory exchange ratio (RER) corresponding to a 13.7% increase in fat utilization as an energy source compared to controls. Female but not male Crym tg mice gained weight more rapidly than controls when fed high fat or high simple carbohydrate diets. Although labeling for myosin heavy chains showed no fiber type differences in TA or soleus muscles, application of machine learning algorithms revealed small but significant morphological differences between Crym tg and control soleus fibers. RNA-seq and gene ontology enrichment analysis showed a significant shift towards genes associated with slower muscle function and its metabolic correlate, β-oxidation. Protein expression showed a similar shift, though with little overlap. Our study shows that μ-crystallin plays an important role in determining substrate utilization in mammalian muscle and that high levels of μ-crystallin are associated with a shift toward greater fat metabolism.
Keywords	Glycolysis ; β-oxidation ; RER ; RNA-seq ; Proteomics ; Thyroid hormone ; Physiology ; QP1-981 ; Specialties of internal medicine ; RC581-951
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Chronic dietary supplementation with soy protein improves muscle function in rats.

Ramzi J Khairallah / Karen M O'Shea / Christopher W Ward / Dustie N Butteiger / Ratna Mukherjea / Elaine S Krul

PLoS ONE, Vol 12, Iss 12, p e

2017 Volume 0189246

Abstract: Athletes as well as elderly or hospitalized patients use dietary protein supplementation to maintain or grow skeletal muscle. It is recognized that high quality protein is needed for muscle accretion, and can be obtained from both animal and plant-based ... ...

Abstract	Athletes as well as elderly or hospitalized patients use dietary protein supplementation to maintain or grow skeletal muscle. It is recognized that high quality protein is needed for muscle accretion, and can be obtained from both animal and plant-based sources. There is interest to understand whether these sources differ in their ability to maintain or stimulate muscle growth and function. In this study, baseline muscle performance was assessed in 50 adult Sprague-Dawley rats after which they were assigned to one of five semi-purified "Western" diets (n = 10/group) differing only in protein source, namely 19 kcal% protein from either milk protein isolate (MPI), whey protein isolate (WPI), soy protein isolate (SPI), soy protein concentrate (SPC) or enzyme-treated soy protein (SPE). The diets were fed for 8 weeks at which point muscle performance testing was repeated and tissues were collected for analysis. There was no significant difference in food consumption or body weights over time between the diet groups nor were there differences in terminal organ and muscle weights or in serum lipids, creatinine or myostatin. Compared with MPI-fed rats, rats fed WPI and SPC displayed a greater maximum rate of contraction using the in vivo measure of muscle performance (p<0.05) with increases ranging from 13.3-27.5% and 22.8-29.5%, respectively at 60, 80, 100 and 150 Hz. When the maximum force was normalized to body weight, SPC-fed rats displayed increased force compared to MPI (p<0.05), whereas when normalized to gastrocnemius weight, WPI-fed rats displayed increased force compared to MPI (p<0.05). There was no difference between groups using in situ muscle performance. In conclusion, soy protein consumption, in high-fat diet, resulted in muscle function comparable to whey protein and improved compared to milk protein. The benefits seen with soy or whey protein were independent of changes in muscle mass or fiber cross-sectional area.
Keywords	Medicine ; R ; Science ; Q
Subject code	796
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress

JCI Insight, Vol 6, Iss

2021 Volume 23

Abstract: Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and ... ...

Abstract	Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current–induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.
Keywords	Cardiology ; Medicine ; R
Subject code	572
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Single-color, ratiometric biosensors for detecting signaling activities in live cells

Brian L Ross / Brian Tenner / Michele L Markwardt / Adam Zviman / Guoli Shi / Jaclyn P Kerr / Nicole E Snell / Jennifer J McFarland / Joseph R Mauban / Christopher W Ward / Megan A Rizzo / Jin Zhang

eLife, Vol

2018 Volume 7

Abstract: Genetically encoded fluorescent biosensors have revolutionized the study of signal transduction by enabling the real-time tracking of signaling activities in live cells. Investigating the interaction between signaling networks has become increasingly ... ...

Abstract	Genetically encoded fluorescent biosensors have revolutionized the study of signal transduction by enabling the real-time tracking of signaling activities in live cells. Investigating the interaction between signaling networks has become increasingly important to understanding complex cellular phenomena, necessitating an update of the biosensor toolkit to allow monitoring and perturbing multiple activities simultaneously in the same cell. We therefore developed a new class of fluorescent biosensors based on homo-FRET, deemed FLuorescence Anisotropy REporters (FLAREs), which combine the multiplexing ability of single-color sensors with a quantitative, ratiometric readout. Using an array of color variants, we were able to demonstrate multiplexed imaging of three activity reporters simultaneously in the same cell. We further demonstrate the compatibility of FLAREs for use with optogenetic tools as well as intravital two-photon imaging.
Keywords	polarization ; signal transduction ; fluorescent proteins ; anisotropy ; kinases ; second messengers ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: X-ROS Signaling: Rapid Mechano-Chemo Transduction in Heart

Prosser, Benjamin L / Christopher W. Ward / W. J. Lederer

Science. 2011 Sept. 9, v. 333, no. 6048

2011

Abstract: We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS ... ...

Abstract	We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where NOX2 is located and sensitizes nearby ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). This triggers a burst of Ca2+ sparks, the elementary Ca2+ release events in heart. Although this stretch-dependent "tuning" of RyRs increases Ca2+ signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca2+ sparks to trigger arrhythmogenic Ca2+ waves. In the mouse model of Duchenne muscular dystrophy, hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca2+ release from the SR. X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca2+ release in the heart and offers fresh therapeutic possibilities.
Keywords	animal models ; calcium ; cardiomyocytes ; cardiomyopathy ; mechanotransduction ; microtubules ; muscular dystrophy ; NADP (coenzyme) ; reactive oxygen species ; ryanodine receptors ; sarcoplasmic reticulum
Language	English
Dates of publication	2011-0909
Size	p. 1440-1445.
Publishing place	American Association for the Advancement of Science
Document type	Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1202768
Database	NAL-Catalogue (AGRICOLA)

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