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34 results on '"Hettinger, Zachary"'

5. Impaired proteostatic mechanisms other than decreased protein synthesis limit old skeletal muscle recovery after disuse atrophy

Author

Fuqua, Jordan D., primary, Lawrence, Marcus M., additional, Hettinger, Zachary R., additional, Borowik, Agnieszka K., additional, Brecheen, Parker L., additional, Szczygiel, Marcelina M., additional, Abbott, Claire B., additional, Peelor, Frederick F., additional, Confides, Amy L., additional, Kinter, Michael, additional, Bodine, Sue C., additional, Dupont‐Versteegden, Esther E., additional, and Miller, Benjamin F., additional

Published
2023
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10. Dynamical modeling reveals RNA decay mediates the effect of matrix stiffness on aged muscle stem cell fate

Author

Hettinger, Zachary R., primary, Hu, Sophia, additional, Mamiya, Hikaru, additional, Sahu, Amrita, additional, Iijima, Hirotaka, additional, Wang, Kai, additional, Gilmer, Gabrielle, additional, Miller, Amanda, additional, Nasello, Gabriele, additional, D’Amore, Antonio, additional, Vorp, David A., additional, Rando, Thomas A., additional, Xing, Jianhua, additional, and Ambrosio, Fabrisia, additional

Published
2023
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16. Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice

Author

Dungan, Cory M., primary, Murach, Kevin A., additional, Zdunek, Christopher J., additional, Tang, Zuo Jian, additional, VonLehmden, Georgia L., additional, Brightwell, Camille R., additional, Hettinger, Zachary, additional, Englund, Davis A., additional, Liu, Zheng, additional, Fry, Christopher S., additional, Filareto, Antonio, additional, Franti, Michael, additional, and Peterson, Charlotte A., additional

Published
2021
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24. Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice.

Author

Dungan, Cory M., Murach, Kevin A., Zdunek, Christopher J., Tang, Zuo Jian, VonLehmden, Georgia L., Brightwell, Camille R., Hettinger, Zachary, Englund, Davis A., Liu, Zheng, Fry, Christopher S., Filareto, Antonio, Franti, Michael, and Peterson, Charlotte A.

Subjects
MUSCLE regeneration, MICE, MYOBLASTS, LABORATORY mice, SKELETAL muscle
Abstract

Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole‐body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi‐weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7‐ or 28 days prior to euthanization. Senescence‐associated β‐Galactosidase positive (SA β‐Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β‐Gal+ cells were also CD11b+ in young and old mice 7‐ and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β‐Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti‐inflammatory macrophages. SA β‐Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q‐treated old mice, muscle regenerated following injury to a greater extent compared to vehicle‐treated old mice, having larger fiber cross‐sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice. [ABSTRACT FROM AUTHOR]

Published
2022
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26. Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading

Author

Lawrence, Marcus M., primary, Van Pelt, Douglas W., additional, Confides, Amy L., additional, Hettinger, Zachary R., additional, Hunt, Emily R., additional, Reid, Justin J., additional, Laurin, Jaime L., additional, Peelor, Frederick F., additional, Butterfield, Timothy A., additional, Miller, Benjamin F., additional, and Dupont-Versteegden, Esther E., additional

Published
2020
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28. Massage as a mechanotherapy promotes skeletal muscle protein and ribosomal turnover but does not mitigate muscle atrophy during disuse in adult rats

Author

Lawrence, Marcus M., primary, Van Pelt, Douglas W., additional, Confides, Amy L., additional, Hunt, Emily R., additional, Hettinger, Zachary R., additional, Laurin, Jaime L., additional, Reid, Justin J., additional, Peelor, Frederick F., additional, Butterfield, Timothy A., additional, Dupont‐Versteegden, Esther E., additional, and Miller, Benjamin F., additional

Published
2020
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31. THE USE OF MECHANOTHERAPY TO PROMOTE THE RECOVERY FROM DISUSE ATROPHY IN AGING RAT SKELETAL MUSCLE

Author

Hettinger, Zachary

Subjects
Skeletal Muscle, Aging, Disuse Atrophy, Single Cell RNA Sequencing, Extracellular Matrix, Innate Immunity, Alternative and Complementary Medicine, Translational Medical Research
Abstract

The combination of age and disuse-related skeletal muscle atrophy predisposes older adults to reduced mobility, loss of independence, and poor quality of life. Poor health outcomes resulting from periods of disuse in older adults are exacerbated by an inability to fully recover, ultimately accelerating geriatric populations towards further functional decline. Aged-related changes to skeletal muscle viscoelastic properties, specifically of muscle extracellular matrix (ECM) stiffness, may not only impact how muscle responds during recovery, but also to interventions intended to augment recovery. Remodeling of muscle ECM in the aged may therefore benefit muscle mass recovery, yet therapies focused on ECM remodeling in aged muscle recovering from disuse are currently lacking. Here we report that muscle stiffness is a significant contributor to how aged muscle responds to mechanical loads, as high loads of cyclic compression preferentially damage aged (30 month) but not adult rat (10 month) gastrocnemius muscle recovering form disuse atrophy. We show that lower loads of cyclic compression serve as a mechanotherapy for skeletal muscle ECM remodeling in aged rats recovering from disuse, in part by reprogramming the cellular transcriptomes of fibro-adipo progenitor cells (FAPs) and macrophages. Lastly, we provide evidence for an age-related impairment to skeletal muscle immune cell activation during the recovery from disuse atrophy, potentially contributing to the impaired recovery of muscle size in the aged. The data presented in these studies demonstrates the dynamic and influential role non-myogenic cells play during the recovery from disuse atrophy, which are strongly influenced by age and can be targeted using mechanotherapy to enhance ECM remodeling.

Published
2021

33. Mitigating skeletal muscle wasting in unloading and augmenting subsequent recovery.

Author

Michel JM, Hettinger Z, Ambrosio F, Egan B, Roberts MD, Ferrando AA, Graham ZA, and Bamman MM

Abstract

Skeletal muscle wasting is the hallmark pathophysiological adaptation to unloading or disuse that demonstrates the dependency on frequent mechanical stimulation (e.g. muscle activation and subsequent loading) for homeostasis of normally load-bearing muscles. In the absence of mitigation strategies, no mammalian organism is resistant to muscle atrophy driven by unloading. Given the profound impact of unloading-induced muscle wasting on physical capacity, metabolic health and immune function; mitigation strategies during unloading and/or augmentation approaches during recovery have broad healthcare implications in settings of bed-bound hospitalization, cast immobilization and spaceflight. This topical review aims to: (1) provide a succinct, state-of-the-field summary of seminal and recent findings regarding the mechanisms of unloading-induced skeletal muscle wasting; (2) discuss unsuccessful vs. promising mitigation and recovery augmentation strategies; and (3) identify knowledge gaps ripe for future research. We focus on the rapid muscle atrophy driven by relatively short-term mechanical unloading/disuse, which is in many ways mechanistically distinct from both hypermetabolic muscle wasting and denervation-induced muscle atrophy. By restricting this discussion to mechanical unloading during which all components of the nervous system remain intact (e.g. without denervation models), mechanical loading requiring motor and sensory neural circuits in muscle remain viable targets for both mitigation and recovery augmentation. We emphasize findings in humans with comparative discussions of studies in rodents which enable elaboration of key mechanisms. We also discuss what is currently known about the effects of age and sex as biological factors, and both are highlighted as knowledge gaps and novel future directions due to limited research., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Published
2024
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34. Dynamical modeling reveals RNA decay mediates the effect of matrix stiffness on aged muscle stem cell fate.

Author

Hettinger ZR, Hu S, Mamiya H, Sahu A, Iijima H, Wang K, Gilmer G, Miller A, Nasello G, Dâ Amore A, Vorp DA, Rando TA, Xing J, and Ambrosio F

Abstract

Loss of muscle stem cell (MuSC) self-renewal with aging reflects a combination of influences from the intracellular (e.g., post-transcriptional modifications) and extracellular (e.g., matrix stiffness) environment. Whereas conventional single cell analyses have revealed valuable insights into factors contributing to impaired self-renewal with age, most are limited by static measurements that fail to capture nonlinear dynamics. Using bioengineered matrices mimicking the stiffness of young and old muscle, we showed that while young MuSCs were unaffected by aged matrices, old MuSCs were phenotypically rejuvenated by young matrices. Dynamical modeling of RNA velocity vector fields in silico revealed that soft matrices promoted a self-renewing state in old MuSCs by attenuating RNA decay. Vector field perturbations demonstrated that the effects of matrix stiffness on MuSC self-renewal could be circumvented by fine-tuning the expression of the RNA decay machinery. These results demonstrate that post-transcriptional dynamics dictate the negative effect of aged matrices on MuSC self-renewal.

Published
2023
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