Neuromuscular junction transmission failure in aging and sarcopenia: The nexus of the neurological and muscular systems

Arnold, W. David; Clark, Brian C.

doi:10.1016/j.arr.2023.101966

Cited by 15 publications

(6 citation statements)

References 92 publications

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“…It is thus not surprising that denervation of muscle fibers with aging is thought to play a very important role in driving hallmark features of aging muscle, including atrophy and fiber type shift (Hepple & Rice, 2016 ). Although impaired neuromuscular junction transmission is considered a plausible contributor to impaired muscle function in aging humans (Arnold & Clark, 2023 ), our understanding of how denervation relates to clinically important changes with aging, such as walking speed, is poorly studied. What we do know comes largely from smaller scale studies.…”

Section: Discussionmentioning

confidence: 99%

Higher expression of denervation‐responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)

Lukasiewicz,

Tranah,

Evans

et al. 2024

Aging Cell

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With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation‐responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation‐responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation‐responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

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Section: Discussionmentioning

confidence: 99%

Higher expression of denervation‐responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)

Lukasiewicz,

Tranah,

Evans

et al. 2024

Aging Cell

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show abstract

“…It is thus not surprising that denervation of muscle fibers with aging is thought to play a very important role in driving hallmark features of aging muscle, including atrophy and fiber type shift 1 . Although impaired neuromuscular junction transmission is considered a plausible contributor to impaired muscle function in aging humans 23 , our understanding of how denervation relates to clinically important changes with aging, such as walking speed, is poorly studied. What we do know comes largely from smaller scale studies.…”

Section: Discussionmentioning

confidence: 99%

Higher Expression of Denervation-responsive Genes is Negatively Associated with Muscle Volume and Performance Traits in the Study of Muscle, Mobility and Aging (SOMMA)

Lukasiewicz,

Tranah,

Evans

et al. 2023

Preprint

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With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8thdecade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calcium-dependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (Chrna1, Chrnd, Chrne), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peakand maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervation-responsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

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“…All these processes, together with inflammation, mitochondrial dysfunction, and oxidative stress, contribute to the degeneration of the NMJ, which may be a cause of the muscle degeneration associated with age [19]. However, whether NMJ degeneration is a cause or a consequence of sarcopenia is still to be resolved and it is a question of particular interest in the field [302].…”

Section: Modeling Aging-related Neuromuscular Junction Degenerationmentioning

confidence: 99%

Leveraging Biomaterial Platforms to Study Aging-Related Neural and Muscular Degeneration

Hidalgo-Alvarez,

Madl

2024

Biomolecules

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Aging is a complex multifactorial process that results in tissue function impairment across the whole organism. One of the common consequences of this process is the loss of muscle mass and the associated decline in muscle function, known as sarcopenia. Aging also presents with an increased risk of developing other pathological conditions such as neurodegeneration. Muscular and neuronal degeneration cause mobility issues and cognitive impairment, hence having a major impact on the quality of life of the older population. The development of novel therapies that can ameliorate the effects of aging is currently hindered by our limited knowledge of the underlying mechanisms and the use of models that fail to recapitulate the structure and composition of the cell microenvironment. The emergence of bioengineering techniques based on the use of biomimetic materials and biofabrication methods has opened the possibility of generating 3D models of muscular and nervous tissues that better mimic the native extracellular matrix. These platforms are particularly advantageous for drug testing and mechanistic studies. In this review, we discuss the developments made in the creation of 3D models of aging-related neuronal and muscular degeneration and we provide a perspective on the future directions for the field.

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Neuromuscular junction transmission failure in aging and sarcopenia: The nexus of the neurological and muscular systems

Cited by 15 publications

References 92 publications

Higher expression of denervation‐responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)

Higher expression of denervation‐responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)

Higher Expression of Denervation-responsive Genes is Negatively Associated with Muscle Volume and Performance Traits in the Study of Muscle, Mobility and Aging (SOMMA)

Leveraging Biomaterial Platforms to Study Aging-Related Neural and Muscular Degeneration

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