Author response: Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration

Abstract

Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the ageassociated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of agerelated neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and postsynaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.

AChRs Degeneration at NMJ in Aging-Associated Sarcopenia–A Systematic Review

“…After further screening of remaining articles, 49 were excluded, in which 23 had no comparisons among different ages, 20 were review papers 4 were conference reports and 2 had no full text access. Therefore, 30 manuscripts were included for the systematic review (Courtney and Steinbach, 1981;Banker et al, 1983;Oda, 1984;Herscovich and Gershon, 1987;Smith and Chapman, 1987;Anis and Robbins, 1988;Smith et al, 1990;Prakash and Sieck, 1998;Connor et al, 2002;Deschenes and Wilson, 2003;Apel et al, 2009;Mcmullen and Andrade, 2009;Suzuki et al, 2009;Kulakowski et al, 2011;Li et al, 2011;Samuel et al, 2012;Cheng et al, 2013;Deschenes et al, 2013;Personius and Parker, 2013;Aare et al, 2016;Willadt et al, 2016;Xie et al, 2016Xie et al, , 2018Hughes et al, 2017;Liu et al, 2017;Snyder-Warwick et al, 2018;Zhao et al, 2018;Soendenbroe et al, 2019Soendenbroe et al, , 2020Uchitomi et al, 2019). The flow chart presenting the selection process is shown in Figure 1.…”

“…The 30 selected studies were conducted from 1981 to 2020: 14 rat studies (Courtney and Steinbach, 1981;Smith and Chapman, 1987;Smith et al, 1990;Prakash and Sieck, 1998;Connor et al, 2002;Deschenes and Wilson, 2003;Apel et al, 2009;Mcmullen and Andrade, 2009;Suzuki et al, 2009;Deschenes et al, 2013;Aare et al, 2016;Xie et al, 2016Xie et al, , 2018Hughes et al, 2017), 13 mouse studies (Banker et al, 1983;Herscovich and Gershon, 1987;Anis and Robbins, 1988;Kulakowski et al, 2011;Li et al, 2011;Samuel et al, 2012;Cheng et al, 2013;Personius and Parker, 2013;Willadt et al, 2016;Liu et al, 2017;Snyder-Warwick et al, 2018;Zhao et al, 2018;Uchitomi et al, 2019) and 3 human studies (Oda, 1984;Soendenbroe et al, 2019Soendenbroe et al, , 2020. The characteristics of the included studies are shown in Table 1.…”

“…Among the 14 rat studies, 6 used the diaphragm (Courtney and Steinbach, 1981;Smith and Chapman, 1987;Smith et al, 1990;Prakash and Sieck, 1998;Suzuki et al, 2009;Xie et al, 2016), 2 used laryngeal muscles (Connor et al, 2002;Mcmullen and Andrade, 2009), 3 used soleus (Deschenes and Wilson, 2003;Apel et al, 2009;Deschenes et al, 2013), 1 used plantaris (Hughes et al, 2017), 2 used gastrocnemius (Apel et al, 2009;Hughes et al, 2017), 3 used tibialis anterior (TA) (Xie et al, 2016(Xie et al, , 2018Hughes et al, 2017), 3 used extensor digitorum longus (EDL) (Deschenes et al, 2013;Hughes et al, 2017;Liu et al, 2017), 2 used vastus lateralis (Aare et al, 2016;Hughes et al, 2017) 1 used semimembranosus (Hughes et al, 2017), and 1 used sternomastoid muscle (Courtney and Steinbach, 1981). Among the 13 mouse studies, 6 used diaphragm (Banker et al, 1983;Herscovich and Gershon, 1987;Samuel et al, 2012;Willadt et al, 2016;Liu et al, 2017;Zhao et al, 2018), 4 used soleus (Banker et al, 1983;Anis and Robbins, 1988;Kulakowski et al, 2011;Personius and Parker, 2013), 3 used gastrocnemius (Herscovich and Gershon, 1987;Zhao et al, 2018;Uchitomi et al, 2019), 4 used TA <...>…”

“…Among the 14 rat studies, 2 used rats from 2-3 to 30 months old (Courtney and Steinbach, 1981;Suzuki et al, 2009), 3 used 9-10 and 28-29 months old rats (Smith and Chapman, 1987;Smith et al, 1990;Hughes et al, 2017), 4 used 24 months old rats as the old group and compared with 4, 6, 8, and 9 months old rats, respectively (Prakash and Sieck, 1998;Connor et al, 2002;Apel et al, 2009;Deschenes et al, 2013), 1 used 6, 18, and 30 months old rats (Mcmullen and Andrade, 2009), 1 used 5 and 20 months old rats (Xie et al, 2016), 1 used 8 and 22 months old rats (Deschenes and Wilson, 2003), 1 used 8 and 35-36 months old rats (Aare et al, 2016), 1 used 4 and 16 months old rats (Xie et al, 2018). Among the 13 mouse studies, 1 used 8-12 and 29-35 months old mice (Banker et al, 1983), 1 used 6 and 28 months old mice (Herscovich and Gershon, 1987), 1 used 7-8 and 24-25 months old mice (Anis and Robbins, 1988), 1 used 12-14 and 26-28 months old mice (Willadt et al, 2016), 2 used 24 months old mice as the old group and compared with 3 and 6 months old mice (Kulakowski et al, 2011;Zhao et al, 2018), 1 used mice from 3 weeks to 26 months old (Li et al, 2011), 1 used 3-4 and 24-28 months old mice (Samuel et al, 2012), 1 used mice from 2 to 28 months old (Cheng et al, 2013), 1 used 3, 12, and 24 months old mice (Personius and Parker, 2013), 1 used 3, 6, 12, 18, and 24 months old mice (Liu et al, 2017), 1 used 8 weeks, 4 and 28 months old mice (Uchitomi et al, 2019), 1 used mice from 3 to 33 months old (Snyder-Warwick et al, 2018). The age range of 3 human studies was 32-76 years, 65-94 years, and 20-90 years old (Oda, 1984;Soendenbroe et al, 2019Soendenbroe et al, , 2020.…”

“…In fast-twitch muscles, sternomastoid muscle and TA, the incidence of fragmented AChRs dramatically increased during aging in mice (Li et al, 2011;Cheng et al, 2013;Liu et al, 2017;Snyder-Warwick et al, 2018;Zhao et al, 2018). Li et al reported the incidence of fragmented junctions (with 10 or more fragments of endplate) increased dramatically from <25% at 18 months to >80% at 22 months in sternomastoid muscle (Li et al, 2011).…”