Nuclear mechanotransduction in skeletal muscle adaptation and aging
Skeletal muscle has the remarkable ability to adapt to mechanical forces – when we do resistance training our muscles get bigger (hypertrophy), but when we age and reduce our activity, they get smaller (atrophy). While there is clear evidence supporting mechanotransduction pathways that stimulate protein synthesis as being central regulators of muscle mass, there are likely additional mechano-sensitive mechanisms important for controlling functional muscle adaptation.
Our lab is focused on understanding the cellular mechanisms that control muscle adaptation, with a specific focus on the cell nucleus. Previously, it was thought that the nucleus was just a passive organelle, simply responsible for housing our genetic material (DNA). However, in recent years it has been shown that the nucleus can directly respond to mechanical forces, a process termed ‘nuclear mechanotransduction’. The importance of nuclear mechanotransduction in cellular function is evident by the various genetic diseases that arise from mutations in proteins crucial to the transduction cascade. Intriguingly, these diseases preferentially affect cardiac and skeletal muscle, suggesting that nuclear mechanotransduction is critically important for striated muscle homeostasis. Our research integrates cell biology, bioengineering and whole-animal physiology approaches to study the role that nuclear mechanotransduction plays in skeletal muscle adaptation and aging.
2019 – 2022 – Career Development Grant, The Muscular Dystrophy Association – DNA-PK hyperactivation in the progression of Emery-Dreifuss muscular dystrophy.
Kirby, T.J.*, A.J. Earle*, G.R. Fedorchak*, P. Isermann, J. Patel, S. Iruvanti, S.A. Moore, G. Bonne, L.L. Wallrath and J. Lammerding. Mutant lamins cause mechanically-induced nuclear envelope rupture and DNA damage in skeletal muscle cells. Nature Materials, 19 (4): 464-473, 2020. PMID: 31844279
Kirby, T.J.*, C.S Fry*, K. Kosmac, J. J. McCarthy, and C. A. Peterson. Myogenic progenitor cells control extracellular matrix production by fibroblasts during skeletal muscle hypertrophy. Cell Stem Cell, 20(1): 56-69, 2017. PMID: 27840022.
Kirby, T.J., R.M. Patel, T. M. McClintock, E. E. Dupont-Versteegden, C. A. Peterson, and J. J. McCarthy. Modulation of global transcriptional output within myogenic cells during hypertrophic growth. Molecular Biology of the Cell, 27(5): 788-798, 2016. PMID: 26764089
Kirby, T.J., J.D. Lee, J.H. England, T. Chaillou, K.A. Esser and J.J. McCarthy. Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis. Journal of Applied Physiology, 119(4): 321-327, 2015. PMID: 26048973
Fry, C.S., J.D. Lee, J. Mula, T.J. Kirby, J.R. Jackson, F. Liu., L. Yang, C.L. Mendias, E. E. Dupont-Versteegden, J. J. McCarthy, and C. A. Peterson. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nature Medicine. 21(1): 76-80, 2015. PMID: 25501907.
* Indicates co-first authorship