Molecular aging and rejuvenation of human muscle stem cells

Abstract

Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-β)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored ‘youthful’ myogenic responses to satellite cells from 70-year-old humans, rendering them similar to cells from 20-year-old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by ‘youthful’ calibration of specific molecular pathways.

Sera from young and older humans equally sustain proliferation and differentiation of human myoblasts

“…Our findings showing no age related impairment in myoblast behaviour in freshly isolated cells are in contrast with results from studies in mice (Carlson et al2007, Brack et al 2007) and humans (Carlson et al 2009) where serum from aged donors decreases the ability of myoblasts from both young and old donors to incorporate BrdU and express the muscle markers, Pax7, Myf5, MyoD, and desmin (Carlson et al 2007, Brack et al 2007. The difference between these findings and our own is difficult …”

“…Subsequently, the onset of expression of myogenic and proliferative markers in the first two days of culture has been shown to be impaired when cells are cultured in serum from older compared to young animals (Carlson & Conboy, 2007). This also appears to be the case when human satellite cells are cultured in serum from young and older people (Carlson et al 2009); although pooled human serum was used in heterochronic experiments experiments (i.e. in which old serum was used on young cells and vice versa), eliminating the possibility for comparison between individual serum donors.…”

“…Indeed, there is evidence of a loss of satellite cells in the muscles of older people (Carlson et al 2009, Kadi et al 2004, Verdijk et al 2007, which seems to be specific to type II fibres (Verdijk et al 2007). In rodents, an age-related impairment of satellite cell mediated muscle repair has been observed in response to severe damage (Conboy et al 2003).…”

Mechanism-Based Therapeutic Approaches to Cachexia

“…Not only, it appears able to counteract the anabolic stimuli induced by treatment with  2 -adrenergic agonists or IGF-1 (Haddad & Adams, 2004;Shi et al, 2007). Consistently, reduced levels of active ERK were reported in sarcopenia of aging (Carlson et al, 2009). ERK inhibition seems required to increase ubiquitin ligase expression in cultured murine myocytes (Shi et al, 2008).…”

“…Finally, muscle atrophy due to immobilization by hind-limb suspension was associated with increased levels of phosphorylated ERK (Kato et al, 2002). As IGF-1, also ERK plays a role in myogenesis, being able to enhance the regenerative capacity of human satellite cells isolated from both young and old subjects (Carlson et al, 2009). Treatment of mice bearing the C26 colon carcinoma with the ERK inhibitor PD98059 partially but significantly protects tumor hosts from the onset of body weight loss and muscle mass depletion .…”