Aging disrupts gene expression timing during muscle regeneration

Kurland, Jesse V.; Cutler, Alecia; Stanley, Jacob T.; Betta, Nicole Dalla; Deusen, Ashleigh Van; Pawlikowski, Brad; Hall, M. N.; Antwine, Tiffany; Russell, Alan J.; Allen, Mary A.; Dowell, Robin D.; Olwin, Bradley B.

doi:10.1016/j.stemcr.2023.05.005

Cited by 5 publications

(2 citation statements)

References 55 publications

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“…These findings are in line with previous reports of the negative regulation of skeletal muscle size, which decreases with aging ( Shavlakadze et al, 2023 ). Overall, the general increase in markers of muscle cell differentiation may reflect a disturbed balance of satellite cell quiescence, activation, and differentiation in aged skeletal muscle ( Chen et al, 2020 ; Kurland et al, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease

Kolonay,

Sattler,

Strawser

et al. 2024

Front. Cell Dev. Biol.

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Genesis of skeletal muscle relies on the differentiation and fusion of mono-nucleated muscle progenitor cells into the multi-nucleated muscle fiber syncytium. The temporally-controlled cellular and morphogenetic changes underlying this process are initiated by a series of highly coordinated transcription programs. At the core, the myogenic differentiation cascade is driven by muscle-specific transcription factors, i.e., the Myogenic Regulatory Factors (MRFs). Despite extensive knowledge on the function of individual MRFs, very little is known about how they are coordinated. Ultimately, highly specific coordination of these transcription programs is critical for their masterfully timed transitions, which in turn facilitates the intricate generation of skeletal muscle fibers from a naïve pool of progenitor cells. The Mediator complex links basal transcriptional machinery and transcription factors to regulate transcription and could be the integral component that coordinates transcription factor function during muscle differentiation, growth, and maturation. In this study, we systematically deciphered the changes in Mediator complex subunit expression in skeletal muscle development, regeneration, aging, and disease. We incorporated our in vitro and in vivo experimental results with analysis of publicly available RNA-seq and single nuclei RNA-seq datasets and uncovered the regulation of Mediator subunits in different physiological and temporal contexts. Our experimental results revealed that Mediator subunit expression during myogenesis is highly dynamic. We also discovered unique temporal patterns of Mediator expression in muscle stem cells after injury and during the early regeneration period, suggesting that Mediator subunits may have unique contributions to directing muscle stem cell fate. Although we observed few changes in Mediator subunit expression in aging muscles compared to younger muscles, we uncovered extensive heterogeneity of Mediator subunit expression in dystrophic muscle nuclei, characteristic of chronic muscle degeneration and regeneration cycles. Taken together, our study provides a glimpse of the complex regulation of Mediator subunit expression in the skeletal muscle cell lineage and serves as a springboard for mechanistic studies into the function of individual Mediator subunits in skeletal muscle.

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Section: Resultsmentioning

confidence: 99%

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease

Kolonay,

Sattler,

Strawser

et al. 2024

Front. Cell Dev. Biol.

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“…[2,3] An excellent example of age-associated stem cell dysfunction occurs in skeletal muscle, where muscle stem cells (MuSCs) undergo increases in chromatin accessibility [4] and genomic interactions [5,6] that drive changes in gene expression. [7,8] The intrinsic changes in MuSCs during aging are also associated with alterations [9,10] in the ECM. [11,12] Old aged skeletal muscle has been shown to lose fibronectin [13] , as well as displays increased stiffness [14] or loss of elasticity [15] from increases in total collagen content [16] and changes in collagen type (increases in Collagen I, III and IV and reductions in collagen VI [17] ).…”

Section: Introductionmentioning

confidence: 99%

Quantification of local matrix deposition during muscle stem cell activation using engineered hydrogels

Duran,

Yang,

Plaster

et al. 2024

Preprint

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Adult stem cells occupy a niche that contributes to their function, but how stem cells remodel their microenvironment remains an open-ended question. Herein, biomaterials-based systems and metabolic labeling were utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts were observed to generate less nascent matrix than muscle resident fibro-adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, the increased nascent matrix deposition was associated with stem cell activation. Reducing the ability to deposit nascent matrix in muscle stem cells attenuated function and mimicked impairments observed from muscle stem cells isolated from old aged muscles, which could be rescued with therapeutic supplementation of insulin-like growth factors. These results highlight how nascent matrix production is critical for maintaining healthy stem cell function.

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Tracking of Nascent Matrix Deposition during Muscle Stem Cell Activation across Lifespan Using Engineered Hydrogels

Duran,

Yang,

Plaster

et al. 2024

Advanced Biology

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Adult stem cells occupy a niche that contributes to their function, but how stem cells rebuild their microenvironment after injury remains an open‐ended question. Herein, biomaterial‐based systems and metabolic labeling are utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts are observed to generate less nascent matrix than muscle resident fibro‐adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, muscle stem cells increased nascent matrix deposition with activation kinetics. Reducing the ability to deposit nascent matrix by an inhibitor of vesicle trafficking (Exo‐1) attenuated muscle stem cell function and mimicked impairments observed from muscle stem cells isolated from old muscles. Old muscle stem cells are observed to deposit less nascent matrix than young muscle stem cells, which is rescued with therapeutic supplementation of insulin‐like growth factors. These results highlight the role of nascent matrix production with muscle stem cell activation.

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Aging disrupts gene expression timing during muscle regeneration

Cited by 5 publications

References 55 publications

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease

Quantification of local matrix deposition during muscle stem cell activation using engineered hydrogels

Tracking of Nascent Matrix Deposition during Muscle Stem Cell Activation across Lifespan Using Engineered Hydrogels

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