Single nuclei profiling identifies cell specific markers of skeletal muscle aging, sarcopenia and senescence

Pérez, Kevin; McGuirr, J; Limbad, Chandani; Tarnopolsky, Mark A.; Jp, Nederveen; Nilsson, Magnus; Campisi, Judith; Melov, Simon

doi:10.1101/2021.01.22.21250336

Cited by 11 publications

(13 citation statements)

References 57 publications

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“…Basal expression of key senescence marker, p21, is low in skeletal muscle of adult mice relative to other tissues, with little‐to‐no change by 27+ months of age (Yousefzadeh et al, 2020 ). However, when assessed via single nuclear RNA‐seq, there is a small population of myonuclei from older individuals that express a relatively high amount of p21 (Perez et al, 2021 ). Further, previous work from our lab shows that human primary myotubes can express high levels of inflammatory cytokines in response to environmental stimuli (Varma et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Twenty‐nine studies measured the aforementioned skeletal muscle characteristics in young and old adults. 42 , 60 , 63 , 65 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 The details of the included studies are shown in Table 2 .…”

Section: Resultsmentioning

confidence: 99%

Myonuclear permanence in skeletal muscle memory: a systematic review and meta‐analysis of human and animal studies

Rahmati

McCarthy

Malakoutinia

2022

J cachexia sarcopenia muscle

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One aspect of skeletal muscle memory is the ability of a previously trained muscle to hypertrophy more rapidly following a period of detraining. Although the molecular basis of muscle memory remains to be fully elucidated, one potential mechanism thought to mediate muscle memory is the permanent retention of myonuclei acquired during the initial phase of hypertrophic growth. However, myonuclear permanence is debated and would benefit from a meta-analysis to clarify the current state of the field for this important aspect of skeletal muscle plasticity. The objective of this study was to perform a meta-analysis to assess the permanence of myonuclei associated with changes in physical activity and ageing. When available, the abundance of satellite cells (SCs) was also considered given their potential influence on changes in myonuclear abundance. One hundred forty-seven peer-reviewed articles were identified for inclusion across five separate meta-analyses; (1-2) human and rodent studies assessed muscle response to hypertrophy; (3-4) human and rodent studies assessed muscle response to atrophy; and (5) human studies assessed muscle response with ageing. Skeletal muscle hypertrophy was associated with higher myonuclear content that was retained in rodents, but not humans, with atrophy (SMD = À0.60, 95% CI À1.71 to 0.51, P = 0.29, and MD = 83.46, 95% CI À649.41 to 816.32, P = 0.82; respectively). Myonuclear and SC content were both lower following atrophy in humans (MD = À11, 95% CI À0.19 to À0.03, P = 0.005, and SMD = À0.49, 95% CI À0.77 to À0.22, P = 0.0005; respectively), although the response in rodents was affected by the type of muscle under consideration and the mode of atrophy. Whereas rodent myonuclei were found to be more permanent regardless of the mode of atrophy, atrophy of ≥30% was associated with a reduction in myonuclear content (SMD = À1.02, 95% CI À1.53 to À0.51, P = 0.0001). In humans, sarcopenia was accompanied by a lower myonuclear and SC content (MD = 0.47, 95% CI 0.09 to 0.85, P = 0.02, and SMD = 0.78, 95% CI 0.37-1.19, P = 0.0002; respectively). The major finding from the present meta-analysis is that myonuclei are not permanent but are lost during periods of atrophy and with ageing. These findings do not support the concept of skeletal muscle memory based on the permanence of myonuclei and suggest other mechanisms, such as epigenetics, may have a more important role in mediating this aspect of skeletal muscle plasticity.

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“…By hybridizing a fluorescent probe to the target RNA, ISH-based approaches (e.g., MERFISH, seqFISH+) quantify gene expression levels using fluorescent signals (Eng et al, 2019;Moffitt et al, 2018). ST analysis has been used to study aging and aging-related diseases in tissues including the brain, muscle, synovium, and joints Hardt et al, 2021;Perez et al, 2021;Vickovic et al, 2022). Since aging is characterized by high spatial heterogeneity, it is promising that combining ST techniques with other data sources (such as single-cell sequencing data) will provide an extensive and comprehensive understanding of the mechanisms that underlie aging.…”

Section: Imaging-based Techniquesmentioning

confidence: 99%

The landscape of aging

Cai

Song

et al. 2022

Sci. China Life Sci.

163

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Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

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Single nuclei profiling identifies cell specific markers of skeletal muscle aging, sarcopenia and senescence

Cited by 11 publications

References 57 publications

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

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

Myonuclear permanence in skeletal muscle memory: a systematic review and meta‐analysis of human and animal studies

The landscape of aging

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