Inactivity is a recognized compounding factor in sarcopenia and muscle weakness in old age. However, while the negative effects of unloading on skeletal muscle in young individuals are well elucidated, only little is known about the consequence of immobilization and the regenerative capacity in elderly individuals. Thus the aim of this study was to examine the effect of aging on changes in muscle contractile properties, specific force, and muscle mass characteristics in 9 old (61–74 yr) and 11 young men (21–27 yr) after 2 wk of immobilization and 4 wk of retraining. Both young and old experienced decreases in maximal muscle strength, resting twitch peak torque and twitch rate of force development, quadriceps muscle volume, pennation angle, and specific force after 2 wk of immobilization (P < 0.05). The decline in quadriceps volume and pennation angle was smaller in old compared with young (P < 0.05). In contrast, only old men experienced a decrease in quadriceps activation. After retraining, both young and old regained their initial muscle strength, but old had smaller gains in quadriceps volume compared with young, and pennation angle increased in young only (P < 0.05). The present study is the first to demonstrate that aging alters the neuromuscular response to short-term disuse and recovery in humans. Notably, immobilization had a greater impact on neuronal motor function in old individuals, while young individuals were more affected at the muscle level. In addition, old individuals showed an attenuated response to retraining after immobilization compared with young individuals.

Key points: In the last decade muscle training performed using a combination of low external loads and partial restriction of blood flow to the exercising limb has gained increasing interest, since it leads to significant gains in muscle strength and muscle mass. The cellular mechanisms responsible for the muscular adaptations induced by this training paradigm are not fully understood. This study shows that 3 weeks of high‐frequency, low‐intensity muscle exercise with partial blood flow restriction induces increases in maximal muscle strength accompanied by highly marked gains in muscle fibre size. Furthermore, the results indicate that these muscular adaptations rely on a considerable upregulation in myogenic satellite cells number, resulting in nuclear addition to the exercised myofibres. The results contribute to a better understanding of the physiological mechanisms underlying the gain in muscle strength and muscle mass observed with blood flow restricted low‐intensity resistance exercise. Abstract  Low‐load resistance training with blood flow restriction has been shown to elicit substantial increases in muscle mass and muscle strength; however, the effect on myogenic stem cells (MSCs) and myonuclei number remains unexplored. Ten male subjects (22.8 ± 2.3 years) performed four sets of knee extensor exercise (20% 1RM) to concentric failure during blood flow restriction (BFR) of the proximal thigh (100 mmHg), while eight work‐matched controls (21.9 ± 3.0 years) trained without BFR (control, CON). Twenty‐three training sessions were performed within 19 days. Maximal isometric knee extensor strength (MVC) was examined pre‐ and post‐training, while muscle biopsies were obtained at baseline (Pre), after 8 days intervention (Mid8) and 3 (Post3) and 10 days (Post10) post training to examine changes in myofibre area (MFA), MSC and myonuclei number. MVC increased by 7.1% (Post5) and 10.6% (Post12) (P < 0.001) with BFR training, while type I and II MFA increased by 38% (Mid8), 35–37% (Post3) and 31–32% (Post10) (P < 0.001). MSCs per myofibre increased with BFR training from 0.10 ± 0.01 (Pre) to 0.38 ± 0.02 (Mid8), 0.36 ± 0.04 (Post3) and 0.25 ± 0.02 (Post10) (P < 0.001). Likewise, myonuclei per myofibre increased from 2.49 ± 0.07 (Pre) to 3.30 ± 0.22 (Mid8), 3.20 ± 0.16 (Post3) and 3.11 ± 0.11 (Post10), (P < 0.01). Although MFA increased in CON at Mid8, it returned to baseline at Post3. No changes in MSC or myonuclei number were observed in CON. This study is the first to show that short‐term low‐load resistance exercise performed with partial blood flow restriction leads to marked proliferation of myogenic stem cells and resulting myonuclei addition in human skeletal muscle, which is accompanied by substantial myofibre hypertrophy.

Very little attention has been given to the combined effects of aging and disuse as separate factors causing deterioration in muscle mechanical function. Thus the purpose of this study was to investigate the effects of 2 wk of immobilization followed by 4 wk of retraining on knee extensor muscle mechanical function (e.g., maximal strength and rapid force capacity) and muscle fiber morphology in 9 old (OM: 67.3 ± 1.3 yr) and 11 young healthy men (YM: 24.4 ± 0.5 yr) with comparable levels of physical activity. Following immobilization, OM demonstrated markedly larger decreases in rapid force capacity (i.e., rate of force development, impulse) than YM (∼20–37 vs. ∼13–16%; P < 0.05). In contrast, muscle fiber area decreased in YM for type I, IIA, and IIx fibers (∼15–30%; P < 0.05), whereas only type IIa area decreased in OM (13.2%; P < 0.05). Subsequent retraining fully restored muscle mechanical function and muscle fiber area in YM, whereas OM showed an attenuated recovery in muscle fiber area and rapid force capacity (tendency). Changes in maximal isometric and dynamic muscle strength were similar between OM and YM. In conclusion, the present data reveal that OM may be more susceptible to the deleterious effects of short-term muscle disuse on muscle fiber size and rapid force capacity than YM. Furthermore, OM seems to require longer time to recover and regain rapid muscle force capacity, which may lead to a larger risk of falling in aged individuals after periods of short-term disuse.

Key points: Elderly individuals require a prolonged recovery phase in order to return to initial muscle mass levels following short‐term immobilisation. The cellular mechanisms responsible for the attenuated re‐growth and associated molecular signalling processes in ageing human skeletal muscle are not fully understood. The main study finding was the observation of a less marked muscle mass recovery after immobilisation in elderly compared to young individuals that was paralleled by an elevation in myogenic precursor cell content in young individuals only, whereas the elderly failed to demonstrate any change in myogenic precursor cells. No age‐related differences were observed in the expression of major myogenic regulating factors known to promote skeletal muscle hypertrophy or satellite cell proliferation (IGF‐1Ea, MGF, MyoD1, myogenin, HGF gene products). In contrast, the expression of myostatin demonstrated a more pronounced up‐regulation following immobilisation along with an attenuated down‐regulation in response to reloading in older compared to young individuals, which may have contributed to the present lack of satellite cell proliferation in ageing muscle. Abstract  Recovery of skeletal muscle mass from immobilisation‐induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility‐induced muscle atrophy. Retraining consisted of 4 weeks of supervised resistive exercise in 9 older (OM: mean age) 67.3, range 61–74 yrs) and 11 young (YM: mean age 24.4, range 21–30 yrs) males. Measures of myofibre area (MFA), Pax7‐positive satellite cells (SCs) associated with type I and type II muscle fibres, as well as gene expression analysis of key growth and transcription factors associated with local skeletal muscle milieu, were performed after 2 weeks immobility (Imm) and following 3 days (+3d) and 4 weeks (+4wks) of retraining. OM demonstrated no detectable gains in MFA (vastus lateralis muscle) and no increases in number of Pax7‐positive SCs following 4wks retraining, whereas YM increased their MFA (P < 0.05), number of Pax7‐positive cells, and had more Pax7‐positive cells per type II fibre than OM at +3d and +4wks (P < 0.05). No age‐related differences were observed in mRNA expression of IGF‐1Ea, MGF, MyoD1 and HGF with retraining, whereas myostatin expression levels were more down‐regulated in YM compared to OM at +3d (P < 0.05). In conclusion, the diminished muscle re‐growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age‐specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age‐related difference in muscle mass recovery.

Important insights concerning the molecular basis of skeletal muscle disuse-atrophy and aging related muscle loss have been obtained in cell culture and animal models, but these regulatory signaling pathways have not previously been studied in aging human muscle. In the present study, muscle atrophy was induced by immobilization in healthy old and young individuals to study the time-course and transcriptional factors underlying human skeletal muscle atrophy. The results reveal that irrespectively of age, mRNA expression levels of MuRF-1 and Atrogin-1 increased in the very initial phase (2–4 days) of human disuse-muscle atrophy along with a marked reduction in PGC-1α and PGC-1β (1–4 days) and a ∼10% decrease in myofiber size (4 days). Further, an age-specific decrease in Akt and S6 phosphorylation was observed in young muscle within the first days (1–4 days) of immobilization. In contrast, Akt phosphorylation was unchanged in old muscle after 2 days and increased after 4 days of immobilization. Further, an age-specific down-regulation of MuRF-1 and Atrogin-1 expression levels was observed following 2 weeks of immobilization, along with a slowing atrophy response in aged skeletal muscle. Neither the immediate loss of muscle mass, nor the subsequent age-differentiated signaling responses could be explained by changes in inflammatory mediators, apoptosis markers or autophagy indicators. Collectively, these findings indicate that the time-course and regulation of human skeletal muscle atrophy is age dependent, leading to an attenuated loss in aging skeletal muscle when exposed to longer periods of immobility-induced disuse.