Abstract
Although denervation has long been implicated in aging muscle, the degree to which it is causes the fiber atrophy seen in aging muscle is unknown. To address this question, we quantified motoneuron soma counts in the lumbar spinal cord using choline acetyl transferase immunhistochemistry and quantified the size of denervated versus innervated muscle fibers in the gastrocnemius muscle using the in situ expression of the denervation-specific sodium channel, Nav1.5, in young adult (YA) and senescent (SEN) rats. To gain insights into the mechanisms driving myofiber atrophy, we also examined the myofiber expression of the two primary ubiquitin ligases necessary for muscle atrophy (MAFbx, MuRF1). MN soma number in lumbar spinal cord declined 27% between YA (638±34 MNs×mm−1) and SEN (469±13 MNs×mm−1). Nav1.5 positive fibers (1548±70 μm2) were 35% smaller than Nav1.5 negative fibers (2367±78 μm2; P<0.05) in SEN muscle, whereas Nav1.5 negative fibers in SEN were only 7% smaller than fibers in YA (2553±33 μm2; P<0.05) where no Nav1.5 labeling was seen, suggesting denervation is the primary cause of aging myofiber atrophy. Nav1.5 positive fibers had higher levels of MAFbx and MuRF1 (P<0.05), consistent with involvement of the proteasome proteolytic pathway in the atrophy of denervated muscle fibers in aging muscle. In summary, our study provides the first quantitative assessment of the contribution of denervation to myofiber atrophy in aging muscle, suggesting it explains the majority of the atrophy we observed. This striking result suggests a renewed focus should be placed on denervation in seeking understanding of the causes of and treatments for aging muscle atrophy.
Highlights
Aging of skeletal muscle is characterized by a decline in mass and function, a process known as sarcopenia [1]
Many ideas continue to be explored concerning the causes of sarcopenia, one of the first and most resilient ideas involves denervation of muscle fibers [2,3], an idea first suggested from a report noting marked alterations in the end plate morphology at the neuromuscular junction with aging [4]
On the basis of the aforementioned uncertainty about the causes of muscle atrophy with sarcopenia, the primary purpose of this study was to evaluate the hypothesis that denervation causes myofiber atrophy in aging muscle, which is one of the most important phenotypes involved in the reduction of muscle mass and strength with aging
Summary
Aging of skeletal muscle is characterized by a decline in mass and function, a process known as sarcopenia [1]. Many ideas continue to be explored concerning the causes of sarcopenia, one of the first and most resilient ideas involves denervation of muscle fibers [2,3], an idea first suggested from a report noting marked alterations in the end plate morphology at the neuromuscular junction with aging [4]. It is striking that the muscle morphological alterations in aging human muscle, e.g., accumulation of severely atrophic angular fibers [14,15,16], are similar to those seen in motoneuron diseases and in experimental models of denervation [17,18,19]. Some fibers in aged muscles express markers of denervation, such as neural cell adhesion molecule [20] and the sodium channel, Nav1.5 [21]. Nav1.5 reappears following denervation in adult muscle [23] and provides an effective method for identifying denervated myofibers in aged muscles
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