Human muscle satellite cells show age-related differential expression of S100B protein and RAGE.

During aging, skeletal muscles show reduced mass and functional capacity largely due to loss of the regenerative ability of satellite cells (SCs), the quiescent stem cells located beneath the basal lamina surrounding each myofiber. While both the external environment and intrinsic properties of SCs appear to contribute to the age-related SC deficiency, the latter ones have been poorly investigated especially in humans. In the present work, we analyzed several parameters of SCs derived from biopsies of vastus lateralis muscle from healthy non-trained young (28.7 ± 5.9 years; n = 10) and aged (77.3 ± 6.4 years; n = 11) people. Compared with young SCs, aged SCs showed impaired differentiation when cultured in differentiation medium, and exhibited the following: (1) reduced proliferation; (2) higher expression levels of S100B, a negative regulator of myoblast differentiation; (3) undetectable levels in growth medium of full-length RAGE (receptor for advanced glycation end products), a multiligand receptor of the immunoglobulin superfamily, the engagement of which enhances myoblast differentiation; and (4) lower expression levels of the transcription factors, MyoD and Pax7. Also, either overexpression of full-length RAGE or knockdown of S100B in aged SCs resulted in enhanced differentiation, while overexpression of either a non-transducing mutant of RAGE (RAGEΔcyto) or S100B in young SCs resulted in reduced differentiation compared with controls. Moreover, while aged SCs maintained the ability to respond to mitogenic factors (e.g., bFGF and S100B), they were no longer able to secrete these factors, unlike young SCs. These data support a role for intrinsic factors, besides the extracellular environment in the defective SC function in aged skeletal muscles.

Effects of local vibrations on skeletal muscle trophism in elderly people: mechanical, cellular, and molecular events.

Several studies have examined the effects of vibrations on muscle mass and performance in young healthy people. We studied the effects of vibrations on muscles of elderly male and female volunteers (65-85 years of age) diagnosed with sarcopenia. We applied mechanical vibrations locally (local vibrational training) to the thigh muscles at 300 Hz for a period of 12 weeks, starting with a session of 15 min stimulation once a week and increasing to three sessions of 15 min per week. Treated muscles displayed enhanced maximal isometric strength and increased content of fast MyHC-2X myosin. Single muscle fiber analysis did not show any change in cross-sectional area or in specific tension. Analysis of transcriptional profiles by microarray revealed changes in gene expression after 12 weeks of local vibrational training. In particular, pathways related with energy metabolism, sarcomeric protein balance and oxidative stress response were affected. We conclude that vibration treatment is effective in counteracting the loss of muscular strength associated with sarcopenia and the mode of action of vibration is based on cellular and molecular changes which do not include increase in fiber or muscle size.

Molecular basis of the myogenic profile of aged human skeletal muscle satellite cells during differentiation.

Sarcopenia is the age-related loss of muscle mass, strength and function. Human muscle proteins are synthesized at a slower rate in the elderly than in young adults, leading to atrophy and muscle mass loss with a decline in the functional capability. Additionally, aging is accompanied by a decrease in the ability of muscle tissue to regenerate following injury or overuse due to the impairment of intervening satellite cells, in which we previously reported oxidative damage evidences. The aim of the present study was to determine the effects of aging on myoblasts and myotubes obtained from human skeletal muscle, and characterize the transcriptional profile as molecular expression patterns in relation to age-dependent modifications in their regenerative capacity. Our data show that the failure to differentiate does not depend on reduced myogenic cell number, but difficulty to complete the differentiation program. Data reported here suggested the following findings: (i) oxidative damage accumulation in molecular substrates, probably due to impaired antioxidant activity and insufficient repair capability, (ii) limited capability of elderly myoblasts to execute a complete differentiation program; restricted fusion, possibly due to altered cytoskeleton turnover and extracellular matrix degradation and (iii) activation of atrophy mechanism by activation of a specific FOXO-dependent program.

Epileptic EEG discharges and short non-convulsive crisis: Influence on cognitive and psychobehavioural functions in youths.

PURPOSE: Learning and behavioural difficulties often occur in benign childhood epilepsy. In recent years, several electroencephalogram (EEG) characteristics have been related to the occurrence of learning and behavioral problems. We determined if the cognitive characteristics of epileptic children depend exclusively on illness factors, or if epileptic electroencephalogram discharges during the crisis contribute to these changes. METHODS: We studied a randomly selected group of 150 youths with short non-convulsive crises, who completed cognitive testing and electroencephalographic studies. The inclusion criteria were: undefined crisis, variations in cognitive function and/or frequent epileptiform discharges on the electroencephalogram. RESULTS: Previous research indicates that the type of epilepsy and the patient's educational level can influence cognitive functioning. The electroencephalographic epileptic discharges during the crisis has been found to influence cognitive transitory functions such as vigilance or swiftness of mental functions. The type of epilepsy is correlated statistically with impairment of learning ability tests: reading (F, 5.487, P = 0.005) and mathematics (F, 3.007, P < or = 0.05). In addition, 40% of the epileptic patients had behavioural disordered versus 16% for the control group (P < 0.02). CONCLUSIONS: Our results show dissociation between the characteristic directly dependent on epilepsy, particularly the type of epilepsy, on stable cognitive functions, such as the progress in school, and the effect of parosystic anomalies or the immediate effect of crisis and EEG dischargeson cognitive processes.

Age-dependent imbalance of the antioxidative system in human satellite cells.

The mature myofibres of human skeletal muscle are surrounded by a type of adult stem cell, known as the satellite cell, which lies outside the sarcolemma but within the basal lamina. These cells remain quiescent until external stimuli trigger their re-entry into the cell cycle. In humans, ageing is characterised by a progressive loss of muscle mass and strength (sarcopenia) associated with a decline in functional ability. One of the possible causes of this decline in muscle performance is a decrease in the antioxidative capacity of skeletal muscle, resulting in an abnormal accumulation of the reactive oxygen species (ROS) critical for cell life. The present study shows that: (i) the antioxidant activity of Catalase and Gluthatione transferase in satellite cells derived from the elderly is drastically reduced compared to that in cells isolated from young individuals; (ii) cell membrane fluidity is considerably different between the two age groups; and (iii) basal [Ca(2+)](i) levels in satellite cells increase significantly in an age-dependent manner. In view of the data obtained, we hypothesise that the destabilising oxidative damage that occurs during ageing in skeletal muscle also affects quiescent satellite cells, which spend their life in close anatomic and functional contact with adult fibres. This status is derived from a decrease in the antioxidative capacity, and may negatively affect the ageing satellite cells ability to repair muscle.

Increased neuromuscular activity causes axonal defects and muscular degeneration.

Before establishing terminal synapses with their final muscle targets, migrating motor axons form en passant synaptic contacts with myotomal muscle. Whereas signaling through terminal synapses has been shown to play important roles in pre- and postsynaptic development, little is known about the function of these early en passant synaptic contacts. Here, we show that increased neuromuscular activity through en passant synaptic contacts affects pre- and postsynaptic development. We demonstrate that in zebrafish twister mutants, prolonged neuromuscular transmission causes motor axonal extension and muscular degeneration in a dose-dependent manner. Cloning of twister reveals a novel, dominant gain-of-function mutation in the muscle-specific nicotinic acetylcholine receptor alpha-subunit, CHRNA1. Moreover, electrophysiological analysis demonstrates that the mutant subunit increases synaptic decay times, thereby prolonging postsynaptic activity. We show that as the first en passant synaptic contacts form, excessive postsynaptic activity in homozygous embryos severely impedes pre- and postsynaptic development, leading to degenerative defects characteristic of the human slow-channel congenital myasthenic syndrome. By contrast, in heterozygous embryos, transient and mild increase in postsynaptic activity does not overtly affect postsynaptic morphology but causes transient axonal defects, suggesting bi-directional communication between motor axons and myotomal muscle. Together, our results provide compelling evidence that during pathfinding, myotomal muscle cells communicate extensively with extending motor axons through en passant synaptic contacts.