Charlotte Suetta

Role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a countermeasure

Aging is characterized by loss of spinal motor neurons (MNs) due to apoptosis, reduced insulin‐like growth factor I signaling, elevated amounts of circulating cytokines, and increased cell oxidative stress. The age‐related loss of spinal MNs is paralleled by a reduction in muscle fiber number and size (sarcopenia), resulting in impaired mechanical muscle performance that in turn leads to a reduced functional capacity during everyday tasks. Concurrently, maximum muscle strength, power, and rate of force development are decreased with aging, even in highly trained master athletes. The impairment in muscle mechanical function is accompanied and partly caused by an age‐related loss in neuromuscular function that comprise changes in maximal MN firing frequency, agonist muscle activation, antagonist muscle coactivation, force steadiness, and spinal inhibitory circuitry. Strength training appears to elicit effective countermeasures in elderly individuals even at a very old age (>80 years) by evoking muscle hypertrophy along with substantial changes in neuromuscular function, respectively. Notably, the training‐induced changes in muscle mass and nervous system function leads to an improved functional capacity during activities of daily living.

Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training

The present study investigated the influence of creatine and protein supplementation on satellite cell frequency and number of myonuclei in human skeletal muscle during 16 weeks of heavy‐resistance training. In a double‐blinded design 32 healthy, male subjects (19–26 years) were assigned to strength training (STR) while receiving a timed intake of creatine (STR‐CRE) (n= 9), protein (STR‐PRO) (n= 8) or placebo (STR‐CON) (n= 8), or serving as a non‐training control group (CON) (n= 7). Supplementation was given daily (STR‐CRE: 6–24 g creatine monohydrate, STR‐PRO: 20 g protein, STR‐CON: placebo). Furthermore, timed protein/placebo intake were administered at all training sessions. Muscle biopsies were obtained at week 0, 4, 8 (week 8 not CON) and 16 of resistance training (3 days per week). Satellite cells were identified by immunohistochemistry. Muscle mean fibre (MFA) area was determined after histochemical analysis. All training regimes were found to increase the proportion of satellite cells, but significantly greater enhancements were observed with creatine supplementation at week 4 (compared to STR‐CON) and at week 8 (compared to STR‐PRO and STR‐CON) (P < 0.01–0.05). At week 16, satellite cell number was no longer elevated in STR‐CRE, while it remained elevated in STR‐PRO and STR‐CON. Furthermore, creatine supplementation resulted in an increased number of myonuclei per fibre and increases of 14–17% in MFA at week 4, 8 and 16 (P < 0.01). In contrast, STR‐PRO showed increase in MFA only in the later (16 week, +8%) and STR‐CON only in the early (week 4, +14%) phases of training, respectively (P < 0.05). In STR‐CRE a positive relationship was found between the percentage increases in MFA and myonuclei from baseline to week 16, respectively (r= 0.67, P < 0.05). No changes were observed in the control group (CON). In conclusion, the present study demonstrates for the first time that creatine supplementation in combination with strength training amplifies the training‐induced increase in satellite cell number and myonuclei concentration in human skeletal muscle fibres, thereby allowing an enhanced muscle fibre growth in response to strength training.

Changes in satellite cells in human skeletal muscle after a single bout of high intensity exercise

No studies to date have reported activation of satellite cells in vivo in human muscle after a single bout of high intensity exercise. In this investigation, eight individuals performed a single bout of high intensity exercise with one leg, the contralateral leg being the control. A significant increase in mononuclear cells staining for the neural cell adhesion molecule (N‐CAM) and fetal antigen 1 (FA1) were observed within the exercised human vastus lateralis muscle on days 4 and 8 post exercise. In addition, a significant increase in the concentration of the FA1 protein was determined in intramuscular dialysate samples taken from the vastus lateralis muscle of the exercising leg (day 0: 1.89 ± 0.82 ng ml−1; day 2: 1.68 ± 0.37 ng ml−1; day 4: 3.26 ± 1.29 ng ml−1, P < 0.05 versus basal; day 8: 4.68 ± 2.06 ng ml−1, P < 0.05 versus basal and control). No change was noted in the control leg. Despite this increase in N‐CAM‐ and FA1‐positive mononuclear cells, an increased expression of myogenin and the neonatal isoform of the myosin heavy chain (MHCn) was not observed. Interestingly, myofibre lesions resulting from extensive damage to the proteins within the myofibre, particularly desmin or dystrophin, were not observed, and hence did not appear to induce the expression of either N‐CAM or FA1. We therefore propose that satellite cells can be induced to re‐enter the cell growth cycle after a single bout of unaccustomed high intensity exercise. However, a single bout of exercise is not sufficient for the satellite cell to undergo terminal differentiation.

Effects of aging on human skeletal muscle after immobilization and retraining

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.

Molecular aging and rejuvenation of human muscle stem cells

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.

Resistance Training in the Early Postoperative Phase Reduces Hospitalization and Leads to Muscle Hypertrophy in Elderly Hip Surgery Patients—A Controlled, Randomized Study

Objectives: To better understand how immobilization and surgery affect muscle size and function in the elderly and to identify effective training regimes.

Mechanical properties and collagen cross-linking of the patellar tendon in old and young men

Age-related loss in muscle mass and strength impairs daily life function in the elderly. However, it remains unknown whether tendon properties also deteriorate with age. Cross-linking of collagen molecules provides structural integrity to the tendon fibrils and has been shown to change with age in animals but has never been examined in humans in vivo. In this study, we examined the mechanical properties and pyridinoline and pentosidine cross-link and collagen concentrations of the patellar tendon in vivo in old (OM) and young men (YM). Seven OM (67 +/- 3 years, 86 +/- 10 kg) and 10 YM (27 +/- 2 years, 81 +/- 8 kg) with a similar physical activity level (OM 5 +/- 6 h/wk, YM 5 +/- 2 h/wk) were examined. MRI was used to assess whole tendon dimensions. Tendon mechanical properties were assessed with the use of simultaneous force and ultrasonographic measurements during ramped isometric contractions. Percutaneous tendon biopsies were taken and analyzed for hydroxylysyl pyridinoline (HP), lysyl pyridinoline (LP), pentosidine, and collagen concentrations. We found no significant differences in the dimensions or mechanical properties of the tendon between OM and YM. Collagen concentrations were lower in OM than in YM (0.49 +/- 0.27 vs. 0.73 +/- 0.14 mg/mg dry wt; P < 0.05). HP concentrations were higher in OM than in YM (898 +/- 172 vs. 645 +/- 183 mmol/mol; P < 0.05). LP concentrations were higher in OM than in YM (49 +/- 38 vs. 16 +/- 8 mmol/mol; P < 0.01), and pentosidine concentrations were higher in OM than in YM (73 +/- 13 vs. 11 +/- 2 mmol/mol; P < 0.01). These cross-sectional data raise the possibility that age may not appreciably influence the dimensions or mechanical properties of the human patellar tendon in vivo. Collagen concentration was reduced, whereas both enzymatic and nonenzymatic cross-linking of concentration was elevated in OM vs. in YM, which may be a mechanism to maintain the mechanical properties of tendon with aging.

Resistance training induces qualitative changes in muscle morphology, muscle architecture, and muscle function in elderly postoperative patients.

Although the negative effects of bed rest on muscle strength and muscle mass are well established, it still remains a challenge to identify effective methods to restore physical capacity of elderly patients recovering from hospitalization. The present study compared different training regimes with respect to muscle strength, muscle fiber size, muscle architecture, and stair walking power in elderly postoperative patients. Thirty-six patients (60-86 yr) scheduled for unilateral hip replacement surgery due to hip osteoarthritis were randomized to either 1) resistance training (RT: 3/wk x 12 wk), 2) electrical stimulation (ES: 1 h/day x 12 wk), or 3) standard rehabilitation (SR: 1 h/day x 12 wk). All measurements were performed at baseline, at 5 wk and 12 wk postsurgery. After 12 wk of resistance training, maximal dynamic muscle strength increased by 30% at 60 degrees /s (P < 0.05) and by 29% at 180 degrees /s (P < 0.05); muscle fiber area increased for type I (+17%, P < 0.05), type IIa (+37%, P < 0.05), and type IIx muscle fibers (+51%, P < 0.05); and muscle fiber pennation angle increased by 22% and muscle thickness increased by 15% (P < 0.05). Furthermore, stair walking power increased by 35% (P < 0.05) and was related to the increase in type II fiber area (r = 0.729, P < 0.05). In contrast, there was no increase in any measurement outcomes with electrical stimulation and standard rehabilitation. The present study is the first to demonstrate the effectiveness of resistance training to induce beneficial qualitative changes in muscle fiber morphology and muscle architecture in elderly postoperative patients. In contrast, rehabilitation regimes based on functional exercises and neuromuscular electrical stimulation had no effect. The present data emphasize the importance of resistance training in future rehabilitation programs for elderly individuals.

Proliferation of myogenic stem cells in human skeletal muscle in response to low-load resistance training with blood flow restriction

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.

Effects of aging on muscle mechanical function and muscle fiber morphology during short-term immobilization and subsequent retraining

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.