Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) Model
Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the <i>mdx</i> mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the <i>Cmah</i> gene...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/18/10841 |
| _version_ | 1797487073349861376 |
|---|---|
| author | Paul Ritter Stefanie Nübler Andreas Buttgereit Lucas R. Smith Alexander Mühlberg Julian Bauer Mena Michael Lucas Kreiß Michael Haug Elisabeth Barton Oliver Friedrich |
| author_facet | Paul Ritter Stefanie Nübler Andreas Buttgereit Lucas R. Smith Alexander Mühlberg Julian Bauer Mena Michael Lucas Kreiß Michael Haug Elisabeth Barton Oliver Friedrich |
| author_sort | Paul Ritter |
| collection | DOAJ |
| description | Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the <i>mdx</i> mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the <i>Cmah</i> gene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of ‘structural weakness’, intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from <i>extensor digitorum longus</i> (EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness in <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> diaphragm was similar to <i>wt</i> mice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced in <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> diaphragm (15% in EDL). Myofibrillar architecture was severely compromised in <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> single fibers of both muscle types, but more pronounced in diaphragm. Our results show that the <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> genotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background. |
| first_indexed | 2024-03-09T23:42:28Z |
| format | Article |
| id | doaj.art-0096212f5481494bb713aa7c78ecce29 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:42:28Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0096212f5481494bb713aa7c78ecce292023-11-23T16:49:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181084110.3390/ijms231810841Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) ModelPaul Ritter0Stefanie Nübler1Andreas Buttgereit2Lucas R. Smith3Alexander Mühlberg4Julian Bauer5Mena Michael6Lucas Kreiß7Michael Haug8Elisabeth Barton9Oliver Friedrich10Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyDepartment of Neurobiology, Physiology and Behavior, University of California, Davis, CA 95618, USAInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyCollege of Health & Human Performance, University of Florida, Gainesville, FL 32611, USAInstitute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str. 3, 91052 Erlangen, GermanyDuchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the <i>mdx</i> mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the <i>Cmah</i> gene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of ‘structural weakness’, intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from <i>extensor digitorum longus</i> (EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness in <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> diaphragm was similar to <i>wt</i> mice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced in <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> diaphragm (15% in EDL). Myofibrillar architecture was severely compromised in <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> single fibers of both muscle types, but more pronounced in diaphragm. Our results show that the <i>mdx Cmah<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mrow><mo>−</mo><mo>/</mo><mo>−</mo></mrow></msup></semantics></math></inline-formula></i> genotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background.https://www.mdpi.com/1422-0067/23/18/10841muscular dystrophyskeletal musclemultiphoton microscopyverniers densitycosine angle sum |
| spellingShingle | Paul Ritter Stefanie Nübler Andreas Buttgereit Lucas R. Smith Alexander Mühlberg Julian Bauer Mena Michael Lucas Kreiß Michael Haug Elisabeth Barton Oliver Friedrich Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) Model International Journal of Molecular Sciences muscular dystrophy skeletal muscle multiphoton microscopy verniers density cosine angle sum |
| title | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) Model |
| title_full | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) Model |
| title_fullStr | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) Model |
| title_full_unstemmed | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) Model |
| title_short | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic <i>mdx</i> (<i>mdx Cmah<sup>−/−</sup></i>) Model |
| title_sort | myofibrillar lattice remodeling is a structural cytoskeletal predictor of diaphragm muscle weakness in a fibrotic i mdx i i mdx cmah sup sup i model |
| topic | muscular dystrophy skeletal muscle multiphoton microscopy verniers density cosine angle sum |
| url | https://www.mdpi.com/1422-0067/23/18/10841 |
| work_keys_str_mv | AT paulritter myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT stefanienubler myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT andreasbuttgereit myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT lucasrsmith myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT alexandermuhlberg myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT julianbauer myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT menamichael myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT lucaskreiß myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT michaelhaug myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT elisabethbarton myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel AT oliverfriedrich myofibrillarlatticeremodelingisastructuralcytoskeletalpredictorofdiaphragmmuscleweaknessinafibroticimdxiimdxcmahsupsupimodel |