Immobility and diminished skeletal muscle recovery with age: the sedentary myoblast

Ten million people in the UK are currently aged 65 or over; this number is projected to double by 2050, with one-quarter of the country aged over 65 years. Unfortunately, healthy life expectancy is not increasing as rapidly as life expectancy itself and as such we need a better understanding of age-related health issues in order to develop appropriate interventions and curb the increasing socio-economic and healthcare implications of increased lifespan.

A progressive decline in muscle mass together with a parallel increase in fat mass are considered hallmark features of the ageing process (Saini et al. 2009). Aside from the metabolic and cardiovascular complications, the specific losses of muscle mass and ultimately of strength (sarcopenia) impact on functional ability, quality of life and morbidity (Saini et al. 2009). This situation can be exacerbated by immobilisations (e.g. falls or hospitalisation), where older individuals require longer recovery phases compared with younger counterparts in order to return to their pre-immobilisation muscle mass and functional capabilities (Carlson et al. 2009). Although declining muscle stem/satellite cell numbers and proliferative capacity are relevant, the mechanisms underpinning this maladaptive recovery of muscle mass with age and immobility are poorly understood (Carlson et al. 2009). A better understanding of the cellular aetiology may therefore elucidate therapeutic interventions to tackle the complications related to increased longevity and associated muscle/functional decrements.

In this issue of The Journal of Physiology, Suetta et al. (2013) present exciting new data demonstrating a significant impact of immobilisation and retraining on skeletal muscle fibre composition and on satellite cell adaptation in biopsies obtained from the vastus lateralis (VL) of 11 young (24.4 years) and 9 older (67.3 years) healthy male participants. The authors report that following immobilisation (2 weeks of randomised, unilateral whole-leg casting) the cross-sectional area of type I and II fibres decreased in both populations. However, following a subsequent intervention protocol of 4 weeks’ supervised unilateral strength training for the immobilised leg, only the young participants recovered the lost myofibre area back to baseline levels. Specifically, this manifested as an increase in the proportion of Pax7-positive cells associated with both type I and II fibres again in the younger participants only.

Most intriguingly, and in contrast to the hypothesised outcome, pre- and post-immobilisation expression of key myogenic genes including IGF-IEa, MGF, MyoD, myogenin, HGF and cMet were not different between young and old participants Furthermore, although retraining impacted on the expression profiles of these genes, once again there was no age-related difference in the gene expression profiles observed. These findings are indicative of an uncoupling of the expression of these genes from the reported reduction in post-immobilisation recovery with ageing. This warrants further investigation at the local and systemic (for IGF, MGF and HGF) protein expression as well as the intracellular signalling levels, as the findings challenge our current perceptions of the regulators of muscle maintenance and recovery with age.

The authors also present an exciting and a contrasting set of data relating to myostatin gene expression, which was suppressed in older versus younger participants at baseline. The authors believe this may be associated with high activity levels of the older participants. An alternative suggestion may be that with age, in healthy, older, active individuals, myostatin is proactively decreased as a protective mechanism in order to delay or to dampen the natural progression of muscle wasting. This warrants more specific investigation. Similarly, the metabolic implications of this finding need exploration, given recent studies by Ryan et al. (2012). These authors reported that basal VL myostatin mRNA levels were negatively associated with glucose utilisation in older sedentary individuals and that exercise and weight loss resulted in down-regulation of myostatin mRNA as well as an improvement in insulin sensitivity in obese older men and women. Although not investigated here, the reduced basal myostatin data in the older group may indeed be associated with high levels of activity and could correlate with improved insulin sensitivity, compared with sedentary counterparts.

Suetta et al. (2013) also found a significant effect of post-immobilisation retraining on myostatin adaptation, with a dramatic and immediate increase in myostatin post immobilisation, together with a reduced down-regulation in response to training in older versus younger participants. The authors suggest that this impaired adaptation of myostatin in older participants may impact on reduced satellite cell proliferation and ultimately reduced (or delayed) recovery of myofibre cross-sectional area following immobility with ageing. Indeed as early as 2006, Amthor et al. (2006) reported that myostatin was capable of inhibiting cell division in Pax7-expressing myoblasts, giving credibility to this notion, although again potentially in the face of an uncoupled response of myogenic regulatory factors in the intact muscle.

To summarise, these investigations suggest that in this study group, myogenic regulatory factors were not different between young and old participants, pre- and post immobilisation or post training. Myofibre cross-sectional area, by contrast, was not recovered following a 4 week training intervention in older participants, whereas this time frame was sufficient for recovery in younger participants. These observations challenge our current concepts of myogenic regulators of muscle mass with age and immobility. Associated with the maladaptive response to retraining with age was a divergence in myostatin gene expression across all implemented interventions. The altered myostatin levels post immobility and retraining were perhaps associated with decreased Pax7 positivity and potentially reduced myofibre cross-sectional areas as a consequence of reduced satellite cell proliferation post exercise intervention.

These findings certainly warrant further definition. Initially and in order to consolidate the reported temporal changes in Pax7 and myostatin gene expression, longer retraining interventions resulting in myofibre recovery in older participants are warranted to examine and validate the interaction with myostatin, Pax7 and attenuated myofibre regrowth in older participants. Ideally, mechanistic studies, although difficult to achieve in human interventions, are also ultimately needed to consolidate these observations. In order to ascertain how these may be achieved, initial studies in satellite cell cultures derived from young and older participants at baseline, post immobility and retraining may provide early mechanistic insight to underpin the reported data. In time, these studies will facilitate the development of rehabilitative countermeasures against dampened skeletal muscle adaptability to retraining with age.