Preventing endothelial cell‐mediated muscle satellite cell dysfunction: a new hot topic?

Abstract

Sarcopenia, comprising a progressive loss of skeletal muscle mass and function (i.e. muscle strength), occurs with advancing age and is accelerated by a variety of diseases, including cardiovascular diseases and diabetes. Sarcopenia causes progressive muscle weakness and fatigue, eventually interfering with an individual’s ability to perform activities of daily living. As such, sarcopenia strongly predicts the risk of falls and related injuries, as well as the consequent risk of disability and death. Interventions that successfully maintain skeletal muscle mass and function with ageing and disease could therefore have significant implications for clinical care and public health strategies. However, a major barrier for developing such interventions is that the molecular mechanisms driving sarcopenia have not been fully elucidated. Maintenance of skeletal muscle mass and function involves a constant flux of muscle cell turnover. Damaged, dysfunctional cells are removed from the tissue via apoptosis, whereas new cells are formed through skeletal muscle satellite cells (MuSCs) either fusing together to form new myotubes that mature into myofibres, or to existing myofibres, thereby promoting muscle growth and repair. Under healthy conditions, MuSCs remain quiescent until activated in response to stimuli such as exercise training or injury, at which time the rate of MuSC activation and maturation is influenced by growth and development-promoting factors secreted from neighbouring cells, including vascular endothelial cells (ECs) (Arsic et al. 2004). With ageing and many disease states, the absolute number of MuSCs is reduced, and the development of MuSCs into the mature form is impaired. These changes result in insufficient regeneration of muscle tissue, leading to the development of sarcopenia. Importantly, diseases/conditions associated with sarcopenia are also typically associated with vascular EC dysfunction, which is characterized by impaired endothelium-dependent dilatation [usually mediated by reduced bioavailability of the vasodilatory and signalling molecule nitric oxide (NO)] and increased production of inflammatory cytokines and damaging free radicals (i.e. oxidative stress). Thus, it follows that these impaired EC phenotypes and alterations in the factors secreted by ECs (the ‘EC secretome’) may mediate, at least in part, the declines in MuSC function that lead to sarcopenia. In a recent article published in The Journal of Physiology, Kargl et al. (2019) aimed to determine whether factors secreted from ECs under unhealthy/dysfunctional conditions influence MuSC function. Human umbilical vein ECs were cultured in media with either normal glucose or high glucose to induce endothelial dysfunction – hyperglycaemia, which occurs with diabetes mellitus and ageing (both commonly associated with sarcopenia) and is known to induce EC dysfunction both in culture and in vivo. As expected, the high glucose-treated ECs emitted higher levels of inflammatory cytokines and the damaging free radical superoxide, and lower levels of growth factors into the culture media compared to the normal glucose-treated ECs, and had a lower abundance of the anti-oxidant superoxide dismutase (SOD) and the NO-producing enzyme endothelial NO synthase, all indicating their appropriate use as a model of decreased endothelial health and function. MuSCs isolated from the vastus lateralis muscle of young healthy individuals were then incubated with either conditioned media (i.e. the media containing increased vs. normal levels of inflammatory cytokines, free radicals and other EC-derived factors) aiming to determine the effects of EC-secreted factors on the growth and development of MuSCs into their mature form. Among their many interesting findings, Kargl et al. (2019) observed that, compared to MuSCs exposed to conditioned media from normal glucose-treated ECs, those exposed to conditioned media from high glucose-treated ECs experienced a decrease in viability mediated by a reduction in key pathways related to protein transcription, including reduced phosphorylation of mitogen-activated protein kinase, an essential regulator of proliferation and cell survival. Additionally, Kargl et al. (2019) found a reduction in markers of MuSC differentiation (e.g. myogen and myosin-heavy chain) in the MuSCs exposed to conditioned media from high glucosecompared to normal glucose-treated ECs. Their study demonstrated that, in vitro, exposure to high glucose influences the EC secretome, which consequently affects MuSC cell growth and differentiation. This is an interesting study design because it isolates the EC-specific effects on MuSC; however, more work is required to determine the effect of the EC secretome on MuSCs in vivo because the factors that are released from ECs may be influenced by other factors in the cellular milieu (e.g. factors released from other cell types). Importantly, the study by Kargl et al. (2019) suggests that interventions aiming to improve endothelial health and the resulting EC secretome (especially by reducing oxidative stress and inflammation) could have downstream effects on the regeneration and maintenance of skeletal muscle function with ageing and certain disease states in which endothelial function is a contributing factor. A variety of healthy lifestyle interventions are recognized as having beneficial effects on endothelial function and maintaining muscle mass and function, although many of them have barriers to implementation at a population-level. For example, aerobic exercise training improves endothelial function and increases lean (muscle) mass and muscle strength but has notoriously low adherence. Additionally, it is difficult for certain diseased populations to exercise at sufficiently high intensities needed to confer benefits. These barriers necessitate developing alternative interventions that promote beneficial physiological adaptations but are more feasible in these populations.