Heightened muscle inflammation susceptibility may impair regenerative capacity in aging humans
Open accessAbstract
The regenerative response of skeletal muscle to mechanically induced damage is impaired with age. Previous work in our laboratory suggests this may result from higher proinflammatory signaling in aging muscle at rest and/or a greater inflammatory response to damage. We, therefore, assessed skeletal muscle proinflammatory signaling at rest and 24 h after unaccustomed, loaded knee extension contractions that induced modest muscle damage (72% increase in serum creatine kinase) in a cohort of 87 adults across three age groups (AGE40, AGE61, and AGE76). Vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-α pathways were determined by quantitative PCR and immunoblot analysis. For in vitro studies, cell signaling and fusion capacities were compared among primary myoblasts from young (AGE28) and old (AGE64) donors treated with TNF-α. Muscle expression was higher (1.5- to 2.1-fold) in AGE76 and AGE61 relative to AGE40 for several genes involved in IL-6, TNF-α, and TNF-like weak inducer of apoptosis signaling. Indexes of activation for the proinflammatory transcription factors signal transducer and activator of transcription-3 and NF-κB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, muscle RING finger 1, and atrogin-1, and increased TNF-like weak inducer of apoptosis receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media and greater NF-κB activation in response to TNF-α treatment (compared with AGE28). We show for the first time that human aging is associated with muscle inflammation susceptibility (i.e., higher basal state of proinflammatory signaling) that is present in both tissue and isolated myogenic cells and likely contributes to the impaired regenerative capacity of skeletal muscle in the older population.
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Inflammatory deregulation and the possible overlap between tumour necrosis factor-α (TNF-α) and transforming growth factor β1 (TGF-β1) signalling may promote survival of FAPs and adipocytic differentiation leading to IMAT development and fat accumulation during sarcopenia.
“Inflammatory deregulation and the possible overlap between tumour necrosis factor‐α (TNF‐α) and transforming growth factor β1 (TGF‐β1) signalling may promote survival of FAPs and adipocytic differentiation leading to IMAT development and fat accumulation during sarcopenia.[ 42 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [42]
NF-κB signaling activation increases muscle protein degradation and inhibits myogenesis, except in very late differentiation where it promotes homeostasis.
“activation of NF-κB signaling increases muscle protein degradation and inhibits myogenesis,(Li, Malhotra, and Kumar 2008;Merritt, Stec, Thalacker-Mercer, Windham, Cross, Shelley, Craig, Kosek, Kim, and Bamman 2013) except in very late differentiation where it promotes homeostasis.(Li, Malhotra, and Kumar 2008)”
From Successful aging: Advancing the science of physical independence in older adults (2015) · cites this paper as Merritt, Stec, Thalacker-Mercer, Windham, Cross, Shelley, Craig, Kosek, Kim, and Bamman 2013
Elevated inflammation during ageing may exacerbate sarcopenia by impairing regenerative capacity of muscle.
“Furthermore, elevated levels of inflammation during ageing may also exacerbate the effects of sarcopenia by impairing the regenerative capacity of muscle [59].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [59]
Chronic inflammation during ageing is associated with increased pro-inflammatory cytokines TNF-α and IL-6 compared to younger individuals due to possible dysregulation in immune cell function.
“On the other hand, chronic inflammation observed during ageing is associated with an increase in pro-inflammatory cytokines (compared to younger individuals) such as TNF-α and IL-6 due to possible dysregulation in immune cell function [59,76].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [59]
Elevations in circulating pro-inflammatory cytokines in older individuals negatively impact muscle regeneration by impairing satellite cell differentiation and fusion and increasing NF-κB activation, contributing to deterioration of muscle mass with age.
“Elevations in circulating pro-inflammatory cytokines reported in older individuals negatively impacts muscle regeneration by impairing satellite cell differentiation and fusion and by increasing NF-κB activation. These factors contribute to deterioration of muscle mass with age [59,77].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [59]
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References 46 · Cited by 127
- Authors
- Merritt, E. K., Stec, M. J., Thalacker-Mercer, A., Windham, S. T., Cross, J. M., Shelley, D. P., Craig Tuggle, S., Kosek, D. J., Kim, J.-S., & Bamman, M. M.
- Affiliations
- University of Alabama at Birmingham (US)
- Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
- Corresponding author
- Bamman, Marcas M.
- Venue
- Journal of Applied Physiology
- Publisher
- American Physiological Society
- Published
- 2013-09-15
- Volume
- 115
- Issue
- 6
- Pages
- 937-948
- ISSN
- 0161-7567 (ISSN-L)
- 8750-7587
- 1522-1601
- PMC
- PMC3764621
- OpenAlex
- W2001325359
- Cited by
- 127
- References
- 46
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 5 · 2023: 13 · 2022: 13 · 2021: 8 · 2020: 12 · 2019: 8 · 2018: 10 · 2017: 13 · 2016: 16 · 2015: 12 · 2014: 5
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Applied Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 RX000305)
- National Institute on Aging (R01AG017896)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- skeletal muscle aging, muscle inflammation, muscle regeneration, exercise-induced muscle damage, IL-6 signaling, TNF signaling, NF-κB activation, STAT3 activation, myoblast fusion, myogenesis, resistance loading, creatine kinase, atrogin-1, MuRF1, vastus lateralis
- MeSH terms
- Adult, Aged, Aging, Female, Humans, Inflammation, Male, Middle Aged, Muscular Atrophy, Regeneration, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Muscle, Skeletal, Inflammation Mediators, Myoblasts, Skeletal, STAT3 Transcription Factor
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