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Article ; Online: The road to physiological maturation of stem cell-derived cardiac muscle runs through the sarcomere.

Metzger, Joseph M

Journal of molecular and cellular cardiology

2022 Volume 170, Page(s) 117–120

Abstract: Recent advances the cardiac biomedical sciences have been propelled forward by the development and implementation of human iPSC-derived cardiac muscle. These notable successes notwithstanding, it is well recognized in the field that a major roadblock ... ...

Abstract	Recent advances the cardiac biomedical sciences have been propelled forward by the development and implementation of human iPSC-derived cardiac muscle. These notable successes notwithstanding, it is well recognized in the field that a major roadblock persists in the lack of full "adult cardiac muscle-like" maturation of hiPSC-CMs. This Perspective centers focus on maturation roadblocks in the essential physiological unit of muscle, the sarcomere. Stalled sarcomere maturation must be addressed and overcome before this elegant experimental platform can reach the mountaintop of making impactful contributions in disease pathogenesis, drug discovery, and in clinical regenerative medicine.
MeSH term(s)	Cell Differentiation/physiology ; Humans ; Induced Pluripotent Stem Cells/physiology ; Myocardium ; Myocytes, Cardiac/physiology ; Sarcomeres
Language	English
Publishing date	2022-06-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2022.06.005
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Book: Cardiac cell and gene transfer

Metzger, Joseph Mark

principles, protocols, and applications

(Methods in molecular biology ; 219)

2003

Author's details	ed. by Joseph M. Metzger
Series title	Methods in molecular biology ; 219
Collection
Keywords	Heart Diseases / therapy ; Gene Therapy ; Transformation, Genetic ; Myocytes, Cardiac / cytology ; Myoblasts / cytology ; Herzkrankheit ; Gentherapie ; Herzmuskelzelle ; Gentransfer
Subject	Genübertragung ; Transfer ; Kardiomyozyt ; Kardialer Myozyt ; Herzmuskelzellen ; Somatische Gentherapie ; Herzerkrankung ; Herzkrankheiten
Language	English
Size	XI, 253 S. : Ill., graph. Darst.
Publisher	Humana Press
Publishing place	Totowa, NJ
Publishing country	United States
Document type	Book
HBZ-ID	HT013668537
ISBN	0-89603-994-3 ; 978-0-89603-994-0
Database	Catalogue ZB MED Medicine, Health

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2003 A 1747	order for loan	Magazin

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Article ; Online: Cardiac myocyte intrinsic contractility and calcium handling deficits underlie heart organ dysfunction in murine cancer cachexia.

Law, Michelle L / Metzger, Joseph M

Scientific reports

2021 Volume 11, Issue 1, Page(s) 23627

Abstract: Cachexia is a muscle wasting syndrome occurring in many advanced cancer patients. Cachexia significantly increases cancer morbidity and mortality. Cardiac atrophy and contractility deficits have been observed in patients and in animal models with cancer ... ...

Abstract	Cachexia is a muscle wasting syndrome occurring in many advanced cancer patients. Cachexia significantly increases cancer morbidity and mortality. Cardiac atrophy and contractility deficits have been observed in patients and in animal models with cancer cachexia, which may contribute to cachexia pathophysiology. However, underlying contributors to decreased in vivo cardiac contractility are not well understood. In this study, we sought to distinguish heart-intrinsic changes from systemic factors contributing to cachexia-associated cardiac dysfunction. We hypothesized that isolated heart and cardiac myocyte functional deficits underlie in vivo contractile dysfunction. To test this hypothesis, isolated heart and cardiac myocyte function was measured in the colon-26 adenocarcinoma murine model of cachexia. Ex vivo perfused hearts from cachectic animals exhibited marked contraction and relaxation deficits during basal and pacing conditions. Isolated myocytes displayed significantly decreased peak contraction and relaxation rates, which was accompanied by decreased peak calcium and decay rates. This study uncovers significant organ and cellular-level functional deficits in cachectic hearts outside of the catabolic in vivo environment, which is explained in part by impaired calcium cycling. These data provide insight into physiological mechanisms of cardiomyopathy in cachexia, which is critical for the ultimate development of effective treatments for patients.
MeSH term(s)	Animals ; Body Weight ; Cachexia/complications ; Cachexia/physiopathology ; Calcium/metabolism ; Cell Line, Tumor ; Heart Failure/etiology ; Humans ; Male ; Mice ; Muscular Atrophy/metabolism ; Myocardial Contraction ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Neoplasms, Experimental/complications ; Neoplasms, Experimental/physiopathology ; Organ Size
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-12-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-02688-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Myofilament-based physiological regulatory compensation preserves diastolic function in failing hearts with severe Ca2+ handling deficits.

Heinis, Frazer I / Thompson, Brian R / Gulati, Rishi / Wheelwright, Matthew / Metzger, Joseph M

JCI insight

2024 Volume 9, Issue 6

Abstract: Severe dysfunction in cardiac muscle intracellular Ca2+ handling is a common pathway underlying heart failure. Here we used an inducible genetic model of severe Ca2+ cycling dysfunction by the targeted temporal gene ablation of the cardiac Ca2+ ATPase, ... ...

Abstract	Severe dysfunction in cardiac muscle intracellular Ca2+ handling is a common pathway underlying heart failure. Here we used an inducible genetic model of severe Ca2+ cycling dysfunction by the targeted temporal gene ablation of the cardiac Ca2+ ATPase, SERCA2, in otherwise normal adult mice. In this model, in vivo heart performance was minimally affected initially, even though Serca2a protein was markedly reduced. The mechanism underlying the sustained in vivo heart performance in the weeks prior to complete heart pump failure and death is not clear and is important to understand. Studies were primarily focused on understanding how in vivo diastolic function could be relatively normal under conditions of marked Serca2a deficiency. Interestingly, data show increased cardiac troponin I (cTnI) serine 23/24 phosphorylation content in hearts upon Serca2a ablation in vivo. We report that hearts isolated from the Serca2-deficient mice retained near normal heart pump functional responses to β-adrenergic stimulation. Unexpectedly, using genetic complementation models, in concert with inducible Serca2 ablation, data show that Serca2a-deficient hearts that also lacked the central β-adrenergic signaling-dependent Serca2a negative regulator, phospholamban (PLN), had severe diastolic dysfunction that could still be corrected by β-adrenergic stimulation. Notably, integrating a serines 23/24-to-alanine PKA-refractory sarcomere incorporated cTnI molecular switch complex in mice deficient in Serca2 showed blunting of β-adrenergic stimulation-mediated enhanced diastolic heart performance. Taken together, these data provide evidence of a compensatory regulatory role of the myofilaments as a critical physiological bridging mechanism to aid in preserving heart diastolic performance in failing hearts with severe Ca2+ handling deficits.
MeSH term(s)	Animals ; Mice ; Calcium/metabolism ; Myofibrils/metabolism ; Sarcoplasmic Reticulum/metabolism ; Heart/physiology ; Heart Failure/metabolism ; Adrenergic Agents/metabolism
Chemical Substances	Calcium (SY7Q814VUP) ; Adrenergic Agents
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.163334
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Article ; Online: Inducing positive inotropy in human iPSC-derived cardiac muscle by gene editing-based activation of the cardiac α-myosin heavy chain.

Bedada, Fikru B / Thompson, Brian R / Mikkila, Jennifer L / Chan, Sunny S-K / Choi, Si Ho / Toso, Erik A / Kyba, Michael / Metzger, Joseph M

Scientific reports

2024 Volume 14, Issue 1, Page(s) 3915

Abstract: Human induced pluripotent stem cells and their differentiation into cardiac myocytes (hiPSC-CMs) provides a unique and valuable platform for studies of cardiac muscle structure-function. This includes studies centered on disease etiology, drug ... ...

Abstract	Human induced pluripotent stem cells and their differentiation into cardiac myocytes (hiPSC-CMs) provides a unique and valuable platform for studies of cardiac muscle structure-function. This includes studies centered on disease etiology, drug development, and for potential clinical applications in heart regeneration/repair. Ultimately, for these applications to achieve success, a thorough assessment and physiological advancement of the structure and function of hiPSC-CMs is required. HiPSC-CMs are well noted for their immature and sub-physiological cardiac muscle state, and this represents a major hurdle for the field. To address this roadblock, we have developed a hiPSC-CMs (β-MHC dominant) experimental platform focused on directed physiological enhancement of the sarcomere, the functional unit of cardiac muscle. We focus here on the myosin heavy chain (MyHC) protein isoform profile, the molecular motor of the heart, which is essential to cardiac physiological performance. We hypothesized that inducing increased expression of α-MyHC in β-MyHC dominant hiPSC-CMs would enhance contractile performance of hiPSC-CMs. To test this hypothesis, we used gene editing with an inducible α-MyHC expression cassette into isogeneic hiPSC-CMs, and separately by gene transfer, and then investigated the direct effects of increased α-MyHC expression on hiPSC-CMs contractility and relaxation function. Data show improved cardiac functional parameters in hiPSC-CMs induced with α-MyHC. Positive inotropy and relaxation was evident in comparison to β-MyHC dominant isogenic controls both at baseline and during pacing induced stress. This approach should facilitate studies of hiPSC-CMs disease modeling and drug screening, as well as advancing fundamental aspects of cardiac function parameters for the optimization of future cardiac regeneration, repair and re-muscularization applications.
MeSH term(s)	Humans ; Induced Pluripotent Stem Cells ; Ventricular Myosins/genetics ; Ventricular Myosins/metabolism ; Ventricular Myosins/pharmacology ; Gene Editing ; Myocardium ; Myocytes, Cardiac/metabolism ; Cell Differentiation ; Myosins/metabolism ; Myosin Heavy Chains/genetics ; Myosin Heavy Chains/metabolism
Chemical Substances	Ventricular Myosins (EC 3.6.1.-) ; Myosins (EC 3.6.4.1) ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2024-02-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-53395-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Sarcomere dynamics revealed by a myofilament integrated FRET-based biosensor in live skeletal muscle fibers.

Martin, Ashley A / Thompson, Brian R / Davis, Jonathan P / Vang, Hluechy / Hahn, Dongwoo / Metzger, Joseph M

Scientific reports

2022 Volume 12, Issue 1, Page(s) 18116

Abstract: The sarcomere is the functional unit of skeletal muscle, essential for proper contraction. Numerous acquired and inherited myopathies impact sarcomere function causing clinically significant disease. Mechanistic investigations of sarcomere activation ... ...

Abstract	The sarcomere is the functional unit of skeletal muscle, essential for proper contraction. Numerous acquired and inherited myopathies impact sarcomere function causing clinically significant disease. Mechanistic investigations of sarcomere activation have been challenging to undertake in the context of intact, live skeletal muscle fibers during real time physiological twitch contractions. Here, a skeletal muscle specific, intramolecular FRET-based biosensor was designed and engineered into fast skeletal muscle troponin C (TnC) to investigate the dynamics of sarcomere activation. In transgenic animals, the TnC biosensor incorporated into the skeletal muscle fiber sarcomeres by stoichiometric replacement of endogenous TnC and did not alter normal skeletal muscle contractile form or function. In intact single adult skeletal muscle fibers, real time twitch contractile data showed the TnC biosensor transient preceding the peak amplitude of contraction. Importantly, under physiological temperatures, inactivation of the TnC biosensor transient decayed significantly more slowly than the Ca
MeSH term(s)	Animals ; Sarcomeres/metabolism ; Myofibrils/metabolism ; Troponin C/metabolism ; Fluorescence Resonance Energy Transfer ; Calcium/metabolism ; Muscle Contraction/physiology ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/metabolism ; Biosensing Techniques
Chemical Substances	Troponin C ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-10-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-21425-8
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Article ; Online: Rapid restitution of contractile dysfunction by synthetic copolymers in dystrophin-deficient single live skeletal muscle fibers.

Hahn, Dongwoo / Quick, Joseph D / Thompson, Brian R / Crabtree, Adelyn / Hackel, Benjamin J / Bates, Frank S / Metzger, Joseph M

Skeletal muscle

2023 Volume 13, Issue 1, Page(s) 9

Abstract: Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, a cytoskeletal protein essential for the preservation of the structural integrity of the muscle cell membrane. DMD patients develop severe skeletal muscle weakness, degeneration, and ... ...

Abstract	Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, a cytoskeletal protein essential for the preservation of the structural integrity of the muscle cell membrane. DMD patients develop severe skeletal muscle weakness, degeneration, and early death. We tested here amphiphilic synthetic membrane stabilizers in mdx skeletal muscle fibers (flexor digitorum brevis; FDB) to determine their effectiveness in restoring contractile function in dystrophin-deficient live skeletal muscle fibers. After isolating FDB fibers via enzymatic digestion and trituration from thirty-three adult male mice (9 C57BL10, 24 mdx), these were plated on a laminin-coated coverslip and treated with poloxamer 188 (P188; PEO
MeSH term(s)	Male ; Animals ; Mice ; Dystrophin/metabolism ; Mice, Inbred mdx ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/metabolism ; Muscle Contraction ; Muscular Dystrophy, Duchenne/metabolism
Chemical Substances	Dystrophin
Language	English
Publishing date	2023-05-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2595637-1
ISSN	2044-5040 ; 2044-5040
ISSN (online)	2044-5040
ISSN	2044-5040
DOI	10.1186/s13395-023-00318-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Duchenne muscular dystrophy: disease mechanism and therapeutic strategies.

Bez Batti Angulski, Addeli / Hosny, Nora / Cohen, Houda / Martin, Ashley A / Hahn, Dongwoo / Bauer, Jack / Metzger, Joseph M

Frontiers in physiology

2023 Volume 14, Page(s) 1183101

Abstract: Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. The identification of the dystrophin gene as central to DMD pathogenesis has led to the ... ...

Abstract	Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. The identification of the dystrophin gene as central to DMD pathogenesis has led to the understanding of the muscle membrane and the proteins involved in membrane stability as the focal point of the disease. The lessons learned from decades of research in human genetics, biochemistry, and physiology have culminated in establishing the myriad functionalities of dystrophin in striated muscle biology. Here, we review the pathophysiological basis of DMD and discuss recent progress toward the development of therapeutic strategies for DMD that are currently close to or are in human clinical trials. The first section of the review focuses on DMD and the mechanisms contributing to membrane instability, inflammation, and fibrosis. The second section discusses therapeutic strategies currently used to treat DMD. This includes a focus on outlining the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, repair, and/or a range of dystrophin-independent approaches. The final section highlights the different therapeutic strategies for DMD currently in clinical trials.
Language	English
Publishing date	2023-06-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1183101
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Inexpensive, serotype-independent protocol for native and bioengineered recombinant adeno-associated virus purification.

Arden, Erik / Metzger, Joseph M

Journal of biological methods

2016 Volume 3, Issue 2

Abstract: Recombinant adeno-associated virus (AAV) is a valuable and often used gene therapy vector. With increased demand for highly purified virus comes the need for a standardized purification procedure that is applicable across many serotypes and includes ... ...

Abstract	Recombinant adeno-associated virus (AAV) is a valuable and often used gene therapy vector. With increased demand for highly purified virus comes the need for a standardized purification procedure that is applicable across many serotypes and includes bioengineered viruses. Currently cesium chloride banding or affinity chromatography are the predominate forms of purification. These approaches expose the final purified virus to toxic contaminants or are highly capsid dependent and may require significant optimization to isolate purified AAV. These methods may also limit crude viral lysate processing volume resulting in a significant loss of viral titer. To circumvent these issues, we have developed an AAV purification protocol independent of toxic compounds, supernatant volume and capsid moiety. This purification method standardizes virus purification across native serotype and bioengineered mosaic capsids.
Language	English
Publishing date	2016-05-03
Publishing country	United States
Document type	Journal Article
ISSN	2326-9901
ISSN	2326-9901
DOI	10.14440/jbm.2016.102
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Article: Influence of the Headgroup on the Interaction of Poly(ethylene oxide)-Poly(propylene oxide) Block Copolymers with Lipid Bilayers

Zhang, Wenjia / Metzger, Joseph M / Hackel, Benjamin J / Bates, Frank S / Lodge, Timothy P

Journal of physical chemistry. 2020 Mar. 16, v. 124, no. 12

2020

Abstract: The lipid headgroup plays an important role in the association of polymers with lipid bilayer membranes. Herein, we report how a glycerol headgroup versus a choline headgroup affects the interaction of poly(ethylene oxide)-b-poly(propylene oxide) (PEO- ... ...

Abstract	The lipid headgroup plays an important role in the association of polymers with lipid bilayer membranes. Herein, we report how a glycerol headgroup versus a choline headgroup affects the interaction of poly(ethylene oxide)-b-poly(propylene oxide) (PEO-PPO) block copolymers with lipid bilayer vesicles. Unilamellar vesicles composed of phosphatidylcholine and phosphatidylglycerol at various molar ratios were used as model membranes. The interactions between the block copolymers and lipid bilayers were quantified by pulsed-field gradient nuclear magnetic resonance (PFG-NMR) based on the distinctly different mobilities of free and bound polymers. All the investigated polymer species showed significantly higher binding with 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) sodium salt (POPG) liposomes than with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes, indicating stronger association with the glycerol headgroup compared to the choline headgroup. This effect did not become significant until the composition of mixed POPC/POPG liposomes contained more than 20 mol % POPG. A plausible explanation for the enhanced polymer binding with POPG invokes the role of hydrogen bonding between the glycerol headgroup and the ether moieties of the polymers.
Keywords	choline ; composite polymers ; glycerol ; hydrogen bonding ; lipid bilayers ; models ; moieties ; nuclear magnetic resonance spectroscopy ; phosphatidylcholines ; polyethylene glycol ; propylene oxide
Language	English
Dates of publication	2020-0316
Size	p. 2417-2424.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5207
DOI	10.1021/acs.jpcb.0c00553
Database	NAL-Catalogue (AGRICOLA)

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