Dilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammation
Abstract Background Skeletal muscle myopathy and exercise intolerance are diagnostic hallmarks of heart failure (HF). However, the molecular adaptations of skeletal muscles during dilated cardiomyopathy (DCM)-mediated HF are not completely understood. Methods Skeletal muscle structure and function w...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Skeletal Muscle |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13395-019-0189-y |
| _version_ | 1819117782338371584 |
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| author | Taejeong Song Palanikumar Manoharan Douglas P. Millay Sheryl E. Koch Jack Rubinstein Judith A. Heiny Sakthivel Sadayappan |
| author_facet | Taejeong Song Palanikumar Manoharan Douglas P. Millay Sheryl E. Koch Jack Rubinstein Judith A. Heiny Sakthivel Sadayappan |
| author_sort | Taejeong Song |
| collection | DOAJ |
| description | Abstract Background Skeletal muscle myopathy and exercise intolerance are diagnostic hallmarks of heart failure (HF). However, the molecular adaptations of skeletal muscles during dilated cardiomyopathy (DCM)-mediated HF are not completely understood. Methods Skeletal muscle structure and function were compared in wild-type (WT) and cardiac myosin binding protein-C null mice (t/t), which develop DCM-induced HF. Cardiac function was examined by echocardiography. Exercise tolerance was measured using a graded maximum treadmill running test. Hindlimb muscle function was assessed in vivo from measurements of plantar flexor strength. Inflammatory status was evaluated from the expression of inflammatory markers and the presence of specific immune cell types in gastrocnemius muscles. Muscle regenerative capacityat days 3, 7, and 14 after eccentric contraction-induced injury was determined from the number of phenotypically new and adult fibers in the gastrocnemius, and functional recovery of plantar flexion torque. Results t/t mice developed DCM-induced HF in association with profound exercise intolerance, consistent with previous reports. Compared to WT, t/t mouse hearts show significant hypertrophy of the atria and ventricles and reduced fractional shortening, both systolic and diastolic. In parallel, the skeletal muscles of t/t mice exhibit weakness and myopathy. Compared to WT, plantar flexor muscles of t/t null mice produce less peak isometric plantar torque (Po), develop torque more slowly (+ dF/dt), and relax more slowly (− dF/dt, longer half-relaxation times,1/2RT). Gastrocnemius muscles of t/t mice have a greater number of fibers with smaller diameters and central nuclei. Oxidative fibers, both type I and type IIa, show significantly smaller cross-sectional areas and more central nuclei. These fiber phenotypes suggest ongoing repair and regeneration under homeostatic conditions. In addition, the ability of muscles to recover and regenerate after acute injury is impaired in t/t mice. Conclusions Our studies concluded that DCM-induced HF induces a unique skeletal myopathy characterized by decreased muscle strength, atrophy of oxidative fiber types, ongoing inflammation and damage under homeostasis, and impaired regeneration after acute muscle injury. Furthermore, this unique myopathy in DCM-induced HF likely contributes to and exacerbates exercise intolerance. Therefore, efforts to develop therapeutic interventions to treat skeletal myopathy during DCM-induced HF should be considered. |
| first_indexed | 2024-12-22T05:38:27Z |
| format | Article |
| id | doaj.art-44a1821af2a34b7dbcfd9f06b9b56e03 |
| institution | Directory Open Access Journal |
| issn | 2044-5040 |
| language | English |
| last_indexed | 2024-12-22T05:38:27Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Skeletal Muscle |
| spelling | doaj.art-44a1821af2a34b7dbcfd9f06b9b56e032022-12-21T18:37:15ZengBMCSkeletal Muscle2044-50402019-01-019111210.1186/s13395-019-0189-yDilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammationTaejeong Song0Palanikumar Manoharan1Douglas P. Millay2Sheryl E. Koch3Jack Rubinstein4Judith A. Heiny5Sakthivel Sadayappan6Heart Lung Vascular Institute, Division of Cardiology, University of CincinnatiDepartment of Molecular Genetics, Biochemistry, and Microbiology, University of CincinnatiDivision of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical CenterHeart Lung Vascular Institute, Division of Cardiology, University of CincinnatiHeart Lung Vascular Institute, Division of Cardiology, University of CincinnatiDepartment of Pharmacology and Systems Physiology, University of CincinnatiHeart Lung Vascular Institute, Division of Cardiology, University of CincinnatiAbstract Background Skeletal muscle myopathy and exercise intolerance are diagnostic hallmarks of heart failure (HF). However, the molecular adaptations of skeletal muscles during dilated cardiomyopathy (DCM)-mediated HF are not completely understood. Methods Skeletal muscle structure and function were compared in wild-type (WT) and cardiac myosin binding protein-C null mice (t/t), which develop DCM-induced HF. Cardiac function was examined by echocardiography. Exercise tolerance was measured using a graded maximum treadmill running test. Hindlimb muscle function was assessed in vivo from measurements of plantar flexor strength. Inflammatory status was evaluated from the expression of inflammatory markers and the presence of specific immune cell types in gastrocnemius muscles. Muscle regenerative capacityat days 3, 7, and 14 after eccentric contraction-induced injury was determined from the number of phenotypically new and adult fibers in the gastrocnemius, and functional recovery of plantar flexion torque. Results t/t mice developed DCM-induced HF in association with profound exercise intolerance, consistent with previous reports. Compared to WT, t/t mouse hearts show significant hypertrophy of the atria and ventricles and reduced fractional shortening, both systolic and diastolic. In parallel, the skeletal muscles of t/t mice exhibit weakness and myopathy. Compared to WT, plantar flexor muscles of t/t null mice produce less peak isometric plantar torque (Po), develop torque more slowly (+ dF/dt), and relax more slowly (− dF/dt, longer half-relaxation times,1/2RT). Gastrocnemius muscles of t/t mice have a greater number of fibers with smaller diameters and central nuclei. Oxidative fibers, both type I and type IIa, show significantly smaller cross-sectional areas and more central nuclei. These fiber phenotypes suggest ongoing repair and regeneration under homeostatic conditions. In addition, the ability of muscles to recover and regenerate after acute injury is impaired in t/t mice. Conclusions Our studies concluded that DCM-induced HF induces a unique skeletal myopathy characterized by decreased muscle strength, atrophy of oxidative fiber types, ongoing inflammation and damage under homeostasis, and impaired regeneration after acute muscle injury. Furthermore, this unique myopathy in DCM-induced HF likely contributes to and exacerbates exercise intolerance. Therefore, efforts to develop therapeutic interventions to treat skeletal myopathy during DCM-induced HF should be considered.http://link.springer.com/article/10.1186/s13395-019-0189-yHeart failureDilated cardiomyopathySkeletal myopathyMuscle contractionExercise |
| spellingShingle | Taejeong Song Palanikumar Manoharan Douglas P. Millay Sheryl E. Koch Jack Rubinstein Judith A. Heiny Sakthivel Sadayappan Dilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammation Skeletal Muscle Heart failure Dilated cardiomyopathy Skeletal myopathy Muscle contraction Exercise |
| title | Dilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammation |
| title_full | Dilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammation |
| title_fullStr | Dilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammation |
| title_full_unstemmed | Dilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammation |
| title_short | Dilated cardiomyopathy-mediated heart failure induces a unique skeletal muscle myopathy with inflammation |
| title_sort | dilated cardiomyopathy mediated heart failure induces a unique skeletal muscle myopathy with inflammation |
| topic | Heart failure Dilated cardiomyopathy Skeletal myopathy Muscle contraction Exercise |
| url | http://link.springer.com/article/10.1186/s13395-019-0189-y |
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