A Neurogenic Perspective of Sarcopenia: Time Course Study of Sciatic Nerves From Aging Mice

Abstract

To elucidate the neural basis for age-related sarcopenia, we quantified morphologic and molecular changes within sciatic nerves of aging male and female C57BL/6J mice aged between 3 and 27 months using immunoblotting, immunohistochemistry, and electron microscopy. Protein analyses by immunoblotting of nerves of male mice aged 4, 15, 18, 22, and 24 months showed increased levels of heavy chain SMI-32-positive neurofilaments, vimentin, tau5, choline acetyltransferase (ChAT), and p62 by 18-22 months. Similar protein increases were seen in 26-month-old compared with 3-month-old female mice. Immunostaining of longitudinal sections of old (27-month-old) male sciatic nerves revealed intense staining for tau5 and p62 that was increased compared with that at 3 months, but there were decreased numbers of axon profiles stained for ChAT or isolectin B4 (motor and sensory axons, respectively). Ultrastructural analysis revealed electron-dense aggregates within axons in peripheral nerves of old male mice; the proportion of axons that contained aggregates more than doubled between 15 and 27 months. Overall, the observed age-related accumulation of many proteins from about 18 months of age onward suggests impaired mechanisms for axonal transport and protein turnover. These peripheral nerve changes may contribute to the morphological and functional muscle deficits associated with sarcopenia.

Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice

“…In addition, a novel time course analysis of aging peripheral nerves of male and female C57BL/6J mice (where sarcopenia was evident) demonstrated increasing levels of many proteins in old sciatic nerves [113]. This recent study, combined with a recent comprehensive study in aging male rats that included transcriptome analysis of sciatic and radial nerves, and gastrocnemius and triceps brachii muscles, combined with imaging of NMJ in EDL and the biceps brachii [7], strongly emphasized age-related changes to the neuromuscular system during sarcopenia.…”

Sarcopenia and dysphagia: Position paper by four professional organizations

“…The number of muscle fibers decreases, atrophy of type II fibers is predominant and remodeling from type II to type I is observed . Deteriorated axonal transport and metabolism in the motor nerves of the corresponding muscles have also been reported …”

“…23 Deteriorated axonal transport and metabolism in the motor nerves of the corresponding muscles have also been reported. 24…”

Biomarkers for Duchenne muscular dystrophy: myonecrosis, inflammation and oxidative stress

“…These altered NMJs affect the associated dystrophic nerve over time, with consequent increased levels of S100 and Tau5 proteins seen by 13 months of age in sciatic nerves of mdx mice (Gordish-Dressman et al, 2018). Such neuronal changes indicate progressive irreversible denervation, often associated with neurodegeneration (Krishnan et al, 2016), that is likely to become pronounced over many years or decades and contribute to the loss of muscle function in DMD patients. These preclinical neuronal changes could prove useful as a biomarker for the longterm consequences of repeated intrinsic myonecrosis in animal studies.…”