Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration

Liu, Wenxuan; Klose, Alanna; Forman, Sophie; Paris, Nicole D.; Wei-LaPierre, Lan; Cortés-López, Mariela; Tan, Aidi; Flaherty, Morgan; Miura, Pedro; Dirksen, Robert T.; Chakkalakal, Joe V.

doi:10.7554/elife.26464

Cited by 134 publications

(168 citation statements)

References 48 publications

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“…2) While NMJs acquire age-related features, the underlying cause of such changes remains debated. In particular, it remains unknown whether NMJs are a focal site of pathology or degenerate due to deleterious changes elsewhere in skeletal muscles, motor neurons or other cells [13–16]. 3) The rate of aging among NMJs located in different muscles, within the same muscle, and even in the same motor unit varies considerably [17].…”

Section: Overview Of Aging Nmjsmentioning

confidence: 99%

NMJ maintenance and repair in aging

Taetzsch

Valdez

2018

Current Opinion in Physiology

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As the final output of the somatic nervous system, the neuromuscular junction (NMJ) is essential for all voluntary movements. The NMJ is also necessary for connected cells to function and survive. Because of this central role, much effort has been devoted to understanding the effects of aging, diseases, and injuries on the NMJ. These efforts have revealed a close relationship between aberrant changes at NMJs and its three cellular components - the presynaptic site on motor axons, the postsynaptic region on muscle fibers and perisynaptic Schwann cells. Here, we review the morphological and molecular changes associated with aging NMJs in rodents and humans. We also provide an overview of factors with potential roles in maintaining and repairing adult and aged NMJs.

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Section: Overview Of Aging Nmjsmentioning

confidence: 99%

NMJ maintenance and repair in aging

Taetzsch

Valdez

2018

Current Opinion in Physiology

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“…Max‐projection z‐stack images of NMJs were generated with ImageJ software. The post‐synaptic side was identified based on the entry of the terminal axon and as the concave side of the NMJ [3,4].…”

Section: Methodsmentioning

confidence: 99%

“…Whole EDL muscle contractility and force generation were analyzed using an ASI muscle contraction system (Aurora Scientific, Aurora, Canada) as described previously [3,4]. Briefly, mice were anaesthetized and TA muscles removed.…”

Section: Methodsmentioning

confidence: 99%

“…Skeletal muscle possesses a remarkable capacity for regeneration, which is mediated by adult resident stem/progenitor cell populations that contribute to repair and maintenance [1–4]. Resident Pax7‐expressing muscle stem cells (satellite cells (SCs)) function as an essential source of myonuclei for the early growth, regeneration and lifelong maintenance of skeletal muscle [2–5].…”

Section: Introductionmentioning

confidence: 99%

“…In response to a degenerative injury, SCs activate and divide to produce myogenic progenitors for myofiber regeneration [2,8,9]. Effective maintenance and responsiveness of quiescent SCs at homeostasis is required for the preservation of skeletal muscle integrity and regenerative potential [4,10]. Disruption of quiescence, and the resulting inappropriate cell cycle entry, has been associated with depletion of the adult SC pool and loss of stem cell regenerative potential [6,10].…”

Section: Introductionmentioning

confidence: 99%

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Castration induces satellite cell activation that contributes to skeletal muscle maintenance

Klose

Liu

Paris

et al. 2018

JCSM Rapid Communications

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Background Sarcopenia, the age-related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. Decreased androgen signaling and deficits in the number and function of SCs are features of aging. Although androgen signaling is known to regulate skeletal muscle, the cellular basis for ADT-induced exacerbation of sarcopenia is unknown. Furthermore, the consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored. Methods We examined SC fate in an androgen-deprived environment using immunofluorescence and fluorescence-activated cell sorting (FACS) with SC-specific markers in young castrated mice. To study the effects of androgen deprivation on SC function and skeletal muscle regenerative capacity, young castrated mice were subjected to experimental regenerative paradigms. SC-derived-cell contributions to skeletal muscle maintenance were examined in castrated Pax7CreER/+; ROSA26mTmG/+ mice. SCs were depleted in Pax7CreER/+; ROSA26DTA/+ mice to ascertain the consequences of SC ablation in sham and castrated skeletal muscles. Confocal immunofluorescence analysis of neuromuscular junctions (NMJs), and assessment of skeletal muscle physiology, contractile properties, and integrity were conducted. Results Castration led to SC activation, however this did not result in a decline in SC function or skeletal muscle regenerative capacity. Surprisingly, castration induced SC-dependent maintenance of young skeletal muscle. The functional dependence of skeletal muscles on SCs in young castrated mice was demonstrated by an increase in SC-derived-cell fusion within skeletal muscle fibers. SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of NMJ-associated myonuclei in skeletal muscles from castrated mice. Conclusion The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs. Considering the well-described age-related decline in SCs, the results in this study highlight the need to devise strategies that promote SC maintenance and activity to attenuate or reverse the progression of sarcopenia in elderly androgen-deprived individuals.

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VEGFA Promotes Skeletal Muscle Regeneration in Aging

et al. 2023

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Aging is associated with loss of skeletal muscle regeneration. Differentially regulated vascular endothelial growth factor (VEGF)A with aging may partially underlies this loss of regenerative capacity. To assess the role of VEGFA in muscle regeneration, young (12–14 weeks old) and old C57BL/6 mice (24,25 months old) are subjected to cryoinjury in the tibialis anterior (TA) muscle to induce muscle regeneration. The average cross‐sectional area (CSA) of regenerating myofibers is 33% smaller in old as compared to young (p < 0.01) mice, which correlates with a two‐fold loss of muscle VEGFA protein levels (p = 0.02). The capillary density in the TA is similar between the two groups. Young VEGFlo mice, with a 50% decrease in systemic VEGFA activity, exhibit a two‐fold reduction in the average regenerating fiber CSA following cryoinjury (p < 0.01) in comparison to littermate controls. ML228, a hypoxia signaling activator known to increase VEGFA levels, augments muscle VEGFA levels and increases average CSA of regenerating fibers in both old mice (25% increase, p < 0.01) and VEGFlo (20% increase, p < 0.01) mice, but not in young or littermate controls. These results suggest that VEGFA may be a therapeutic target in age‐related muscle loss.

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Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration

Cited by 134 publications

References 48 publications

NMJ maintenance and repair in aging

NMJ maintenance and repair in aging

Castration induces satellite cell activation that contributes to skeletal muscle maintenance

VEGFA Promotes Skeletal Muscle Regeneration in Aging

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