Age-related gene expression signatures from limb skeletal muscles and the diaphragm in mice and rats reveal common and species-specific changes

Shavlakadze, Tea; Xiong, Kaixin; Mishra, Shawn; McEwen, Corissa; Gadi, Abhilash; Wakai, Matthew; Salmon, Hannah; Stec, Michael J.; Negron, Nicole; Ni, Min; Wei, Yi; Atwal, Gurinder S.; Bai, Yu; Glass, David J.

doi:10.1186/s13395-023-00321-3

Cited by 12 publications

(9 citation statements)

References 52 publications

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“…Skeletal muscle atrophy is a hallmark of aging and is characterized by muscle weakness and decreased metabolic flexibility and is also associated with gene expression changes ( Distefano and Goodpaster, 2018 ; Naruse et al, 2023 ; Shavlakadze et al, 2023 ). To determine how Mediator complex subunit expression is altered in aging muscles and could contribute to the muscle aging process we analyzed RNA-seq data from 10- and 30-months-old male mouse muscles.…”

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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“…We also chose to probe genes associated with various paradigms of muscle loss. Specifically, we investigated genes commonly associated with the ubiquitin–proteasome system, genes associated with various forms of muscle atrophy and well‐known markers of disuse caused by denervation or nerve silencing previously reported by our group and others 38–41 . Despite no histological evidence of denervation in the mouse, we sought to investigate any transcriptional changes that may infer that the muscle is programmed not to grow, despite a large number of anabolic gene signatures (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…Whether the mouse is a suitable model to study human muscle growth or wasting is an important and current research question. A recent transcriptomic survey of 4 muscles in mice and rats across the lifespan, suggests that rats mimic human aging and sarcopenia more closely than mouse 38 . Large differences in the progressive dysregulation of genes associated with metabolic processes and mitochondrial function were found in rat, but not in mouse suggesting that the use of the mouse or mouse tissue must be carefully interpreted when translating to aspects of human aging and sarcopenia.…”

Section: Discussionmentioning

confidence: 99%

Conserved and species‐specific transcriptional responses to daily programmed resistance exercise in rat and mouse

Viggars,

Sutherland,

Cardozo

et al. 2023

The FASEB Journal

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Mice are often used in gain or loss of function studies to understand how genes regulate metabolism and adaptation to exercise in skeletal muscle. Once‐daily resistance training with electrical nerve stimulation produces hypertrophy of the dorsiflexors in rat, but not in mouse. Using implantable pulse generators, we assessed the acute transcriptional response (1‐h post‐exercise) after 2, 10, and 20 days of training in free‐living mice and rats using identical nerve stimulation paradigms. RNA sequencing revealed strong concordance in the timecourse of many transcriptional responses in the tibialis anterior muscles of both species including responses related to “stress responses/immediate‐early genes, and “collagen homeostasis,” “ribosomal subunits,” “autophagy,” and “focal adhesion.” However, pathways associated with energy metabolism including “carbon metabolism,” “oxidative phosphorylation,” “mitochondrial translation,” “propanoate metabolism,” and “valine, leucine, and isoleucine degradation” were oppositely regulated between species. These pathways were suppressed in the rat but upregulated in the mouse. Our transcriptional analysis suggests that although many pathways associated with growth show remarkable similarities between species, the absence of an actual growth response in the mouse may be because the mouse prioritizes energy metabolism, specifically the replenishment of fuel stores and intermediate metabolites.

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“…Whether the mouse is a suitable model to study human muscle growth or wasting is an important and current research question. A recent transcriptomic survey of 4 muscles in mice and rats across the lifespan, suggests that rats mimic human aging and sarcopenia more closely than mouse 35 . Large differences in the progressive dysregulation of genes associated with metabolic processes and mitochondrial function were found in rat, but not in mouse suggesting that the use of the mouse or mouse tissue must be carefully interpreted when translating to aspects of human aging and sarcopenia.…”

Section: Discussionmentioning

confidence: 99%

“…Lastly, we chose to probe genes associated with muscle loss. Specifically we investigated genes commonly associated with the ubiquitin-proteasome system, genes associated with various forms of muscle atrophy and well-known markers of disuse caused by denervation or nerve silencing previously reported by our group and others [35][36][37][38] . Despite no histological evidence of denervation in the mouse, we sought to investigate any transcriptional changes that may infer that the muscle is programmed not to grow, despite a large number of anabolic gene signatures (Figure 3).…”

Section: Insert Figurementioning

confidence: 99%

Conserved and species-specific transcriptional responses to daily programmed resistance exercise in rat and mouse

Viggars,

Sutherland,

Cardozo

et al. 2023

Preprint

View full text Add to dashboard Cite

Mice are often used in gain or loss of function studies to understand how genes regulate metabolism and adaptation to exercise in skeletal muscle. Once-daily resistance training with electrical nerve stimulation produces hypertrophy of the dorsiflexors in rat, but not in mouse. Using implantable pulse generators, we assessed the acute transcriptional response (1-hour post exercise) after 2, 10 and 20 days of training in free living mice and rats using identical nerve stimulation paradigms. RNA-sequencing revealed strong concordance in the timecourse of many transcriptional responses in the tibialis anterior muscles of both species including responses related to 'stress responses/immediate-early genes', and 'collagen homeostasis', 'ribosomal subunits', 'autophagy' and 'focal adhesion'. However, pathways associated with energy metabolism including 'carbon metabolism', 'oxidative phosphorylation', 'mitochondrial translation', 'propanoate metabolism' and 'valine, leucine and isoleucine degradation' were oppositely regulated between species. These pathways were suppressed in the rat but upregulated in the mouse. Our transcriptional analysis suggests that although many pathways associated with growth show remarkable similarities between species, absence of an actual growth response in the mouse may be because the mouse prioritises energy metabolism, specifically replenishment of fuel stores and intermediate metabolites.

show abstract

Age-related gene expression signatures from limb skeletal muscles and the diaphragm in mice and rats reveal common and species-specific changes

Cited by 12 publications

References 52 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

Conserved and species‐specific transcriptional responses to daily programmed resistance exercise in rat and mouse

Conserved and species-specific transcriptional responses to daily programmed resistance exercise in rat and mouse

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