Failed reinnervation in aging skeletal muscle

Abstract

BackgroundSkeletal muscle displays a marked accumulation of denervated myofibers at advanced age, which coincides with an acceleration of muscle atrophy.MethodsIn this study, we evaluated the hypothesis that the accumulation of denervated myofibers in advanced age is due to failed reinnervation by examining muscle from young adult (YA) and very old (VO) rats and from a murine model of sporadic denervation secondary to neurotrypsin over-expression (Sarco mouse).ResultsBoth aging rat muscle and Sarco mouse muscle exhibited marked fiber-type grouping, consistent with repeating cycles of denervation and reinnervation, yet in VO muscle, rapsyn at the endplate increased and was associated with only a 10 % decline in acetylcholine receptor (AChR) intensity, whereas in Sarco mice, there was a decline in rapsyn and a 25 % decrease in AChR intensity. Transcripts of muscle-specific kinase (21-fold), acetylcholine receptor subunits α (68-fold), ε (threefold) and γ (47-fold), neural cell adhesion molecule (66-fold), and runt-related transcription factor 1 (33-fold) were upregulated in VO muscle of the rat, consistent with the marked persistent denervation evidenced by a large proportion of very small fibers (>20 %). In the Sarco mice, there were much smaller increases in denervation transcripts (0–3.5-fold) and accumulation of very small fibers (2–6 %) compared to the VO rat, suggesting a reduced capacity for reinnervation in aging muscle. Despite the marked persistent denervation in the VO rat muscle, transcripts of neurotrophins involved in promoting axonal sprouting following denervation exhibited no increase, and several miRNAs predicted to suppress neurotrophins were elevated in VO rat.ConclusionsOur results support the hypothesis that the accumulation of denervated fibers with aging is due to failed reinnervation and that this may be affected by a limited neurotrophin response that mediates axonal sprouting following denervation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0101-y) contains supplementary material, which is available to authorized users.

Effect of very old age on anconeus motor unit loss and compensatory remodelling

“…However, the S‐MUP amplitudes were not larger in the older group. This is an important and unique finding in humans gained by testing very old men but has support from reports in animal models that reinnervation is compromised in very old rat muscles . Although it seems unlikely, given the results of prior studies in other limb muscles, another possible explanation is that the anconeus is unique and may not undergo typical age‐related remodeling processes.…”

“…In very old animals (e.g., > 30 months in rats) and humans (>85 years), reinnervation of denervated muscle may become significantly compromised, leading to severe sarcopenia . Indeed, failure in the reinnervation process has been demonstrated recently in very old rat (35 months) lower limb muscles …”

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

“…These genes have been used as markers of myofiber denervation because their expression increases in surgically denervated muscles [114–120]. Importantly, increased expression of these genes also has been reported in old rodent skeletal muscle and is proposed to be associated with disturbances to the NMJ and myofiber denervation [7, 48, 49, 116, 121]. Increased mRNA levels for Chrng , Chrnd , Musk , and Myog are reported for old male SD rat gastrocnemius muscles from as early as 12 months of age (although for most at 18–21 months), with progressive increases up to 27 months age [49].…”

“…A recent report by Aare et al . (2016) also shows that Chrng , Musk , and Runx1 mRNA amounts are upregulated in the vastus lateralis muscles of male F344BN rats between 8 and 35–36 months of age [121]. We have earlier demonstrated a significant increase in Chrng , Chrnd , Myog , Gadd45α , and Runx1 expression in the quadriceps muscles of female C57BL/6J mice between 15 and 24 months although expression of these genes became highly variable at later ages (27–29 months) [48].…”

Muscle atrophy and regeneration associated with behavioural loss and recovery of function after sciatic nerve crush

“…Denervation is a common course for disrupted function of skeletal muscles and it may origin in a trauma (ie, mechanical lesioning of the nerve trunk), infections, systemic diseases affecting, eg, the microvasculature of the peripheral nerves or diseases like amyotrophic lateral sclerosis . Denervation may also be a driving force in the loss of skeletal muscle strength and mass during normal ageing, ie, sarcopenia …”