Aged skeletal muscle retains the ability to fully regenerate functional architecture

Abstract

While the general understanding of muscle regenerative capacity is that it declines with increasing age due to impairments in the number of muscle progenitor cells and interaction with their niche, studies vary in their model of choice, indices of myogenic repair, muscle of interest and duration of studies. We focused on the net outcome of regeneration, functional architecture, compared across three models of acute muscle injury to test the hypothesis that satellite cells maintain their capacity for effective myogenic regeneration with age. Muscle regeneration in extensor digitorum longus muscle (EDL) of young (3 mo-old), old (22 mo-old) and senescent female mice (28 mo-old) was evaluated for architectural features, fiber number and central nucleation, weight, collagen and fat deposition. The 3 injury paradigms were: a myotoxin (notexin) which leaves the blood vessels and nerves intact, freezing (FI) that damages local muscle, nerve and blood vessels and denervation-devascularization (DD) which dissociates the nerves and blood vessels from the whole muscle. Histological analyses revealed successful architectural regeneration following notexin injury with negligible fibrosis and fully restored function, regardless of age. In comparison, the regenerative response to injuries that damaged the neurovascular supply (FI and DD) was less effective, but similar across the ages. The focus on net regenerative outcome demonstrated that old and senescent muscle has a robust capacity to regenerate functional architecture.

Exercise conditioning in old mice improves skeletal muscle regeneration

“…Therefore, it is possible that the smaller fiber CSA observed in the O‐Sed group was not simply a result of a delay in muscle regeneration but also that it may never be fully re‐establish in light of the slowing indices of regeneration observed in this group. These findings are contradictory to previous work that reported a re‐establishment of fiber CSA after injury in old mice (8). These authors induced injury via notexin, which causes degeneration via a mechanism similar to that of CTX (31); however, use of different protocols may explain differences observed between studies as, unlike the current study, injury was induced in the extensor digitorum longus of female C57BL/6J mice.…”

“…In addition to muscle fiber CSA, we also aimed to determine the composition of skeletal muscle. Previous work has reported an increase in fibrotic index in the early days after muscle injury in old mice (14); however, when regeneration is followed to later time points (i.e., 30 d after notexin injury), there were no observed differences in fibrotic index between young and old animals (8). Our results are in accordance with both of these studies.…”

“…Complete regeneration of muscle after injury in old mice has been observed (8, 10, 11), whereas others report incomplete or delayed regeneration (12–14). More specifically, some studies demonstrate that, although early regeneration is impaired in old mice, regeneration occurs to the same extent in both young and old mice when examined at later time points (8, 10, 11). These studies underpin the notion that delays in inflammatory response and angiogenesis account for early, impaired regenerative response observed in old mice (10, 11).…”

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

“…In line with previous studies (Bernet et al, 2014; Brack et al, 2007; Chakkalakal, Jones, Basson, & Brack, 2012; Conboy, Conboy, Smythe, & Rando, 2003; Cosgrove et al, 2014; Lee et al, 2013; Shavlakadze, McGeachie, & Grounds, 2010; Sousa‐Victor et al, 2014), we found that muscle regeneration after cardiotoxin (CTX) injury is delayed in male aged animals (Figure 1a–c), as shown by the distribution of the cross‐sectional area (CSA; Supporting information Figure S1A–D), the mean CSA (Figure 1b), the increase in necrotic fiber content at Day 8 post‐CTX (Figure 1c), and the muscle mass alterations during the regeneration process (Figure 1d).…”

The effect of calorie restriction on mouse skeletal muscle is sex, strain and time-dependent

“…Studies on muscle regeneration have been done on C57Bl/6 mice of different sexes 51–54 . Studies on ageing have been mostly done on male C57Bl/6 mice 47, 55, 56 .…”