Aging and skeletal muscle force control: Current perspectives and future directions.

During voluntary muscle contractions, force output is characterized by constant inherent fluctuations, which can be quantified either according to their magnitude or temporal structure, that is, complexity. The presence of such fluctuations when targeting a set force indicates that control of force is not perfectly accurate, which can have significant implications for task performance. Compared to young adults, older adults demonstrate a greater magnitude and lower complexity in force fluctuations, indicative of decreased steadiness, and adaptability of force output, respectively. The nature of this loss-of-force control depends not only on the age of the individual but also on the muscle group performing the task, the intensity and type of contraction and whether the task is performed with additional cognitive load. Importantly, this age-associated loss-of-force control is correlated with decreased performance in a range of activities of daily living and is speculated to be of greater importance for functional capacity than age-associated decreases in maximal strength. Fortunately, there is evidence that acute physical activity interventions can reverse the loss-of-force control in older individuals, though whether this translates to improved functional performance and whether lifelong physical activity can protect against the changes have yet to be established. A number of mechanisms, related to both motor unit properties and the behavior of motor unit populations, have been proposed for the age-associated changes in force fluctuations. It is likely, though, that age-associated changes in force control are related to increased common fluctuations in the discharge times of motor units

Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, we over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD. RET is dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of either RET9 or RET51 increased myoblast proliferation, whereas siRNA-mediated knockdown of Ret induced myogenic differentiation. Suppressing RET activity using Sunitinib, a clinically- approved tyrosine kinase inhibitor, rescued differentiation in both DUX4-expressing murine myoblasts and in FSHD patient-derived myoblasts. Importantly, Sunitinib also increased engraftment and differentiation of FSHD myoblasts in regenerating mouse muscle. Thus, DUX4-mediated activation of Ret prevents myogenic differentiation and could contribute to FSHD pathology by preventing satellite cell-mediated repair. Rescue of DUX4-induced pathology by Sunitinib highlights the therapeutic potential of tyrosine kinase inhibitors for treatment of FSHD

Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration-probing the role of PPARα.

Dietary inorganic nitrate prevents aspects of cardiac mitochondrial dysfunction induced by hypoxia, although the mechanism is not completely understood. In both heart and skeletal muscle, nitrate increases fatty acid oxidation capacity, and in the latter case, this involves up-regulation of peroxisome proliferator-activated receptor (PPAR)α expression. Here, we investigated whether dietary nitrate modifies mitochondrial function in the hypoxic heart in a PPARα-dependent manner. Wild-type (WT) mice and mice without PPARα (Ppara-/-) were given water containing 0.7 mM NaCl (control) or 0.7 mM NaNO3 for 35 d. After 7 d, mice were exposed to normoxia or hypoxia (10% O2) for the remainder of the study. Mitochondrial respiratory function and metabolism were assessed in saponin-permeabilized cardiac muscle fibers. Environmental hypoxia suppressed mass-specific mitochondrial respiration and additionally lowered the proportion of respiration supported by fatty acid oxidation by 18% (P < 0.001). This switch away from fatty acid oxidation was reversed by nitrate treatment in hypoxic WT but not Ppara-/- mice, indicating a PPARα-dependent effect. Hypoxia increased hexokinase activity by 33% in all mice, whereas lactate dehydrogenase activity increased by 71% in hypoxic WT but not Ppara-/- mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodeling in response to both hypoxia and dietary nitrate supplementation.-Horscroft, J. A., O'Brien, K. A., Clark, A. D., Lindsay, R. T., Steel, A. S., Procter, N. E. K., Devaux, J., Frenneaux, M., Harridge, S. D. R., Murray, A. J. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration-probing the role of PPARα

High Levels of Physical Activity in Later Life Are Associated With Enhanced Markers of Mitochondrial Metabolism

The age-associated reduction in muscle mass is well characterized; however, less is known regarding the mechanisms responsible for the decline in oxidative capacity also observed with advancing age. The purpose of the current study was therefore to compare mitochondrial gene expression and protein content between young and old recreationally active, and older highly active individuals. Muscle biopsies were obtained from the vastus lateralis of young males (YG: 22 ± 3 years) and older (OG: 67 ± 2 years) males not previously engaged in formal exercise and older male master cyclists (OT: 65 ± 5 years) who had undertaken cycling exercise for 32 ± 17 years. Comparison of gene expression between YG, OG, and OT groups revealed greater expression of mitochondrial-related genes, namely, electron transport chain (ETC) complexes II, III, and IV (p &amp;lt; .05) in OT compared with YG and OG. Gene expression of mitofusion (MFN)-1/2, mitochondrial fusion genes, was greater in OT compared with OG (p &amp;lt; .05). Similarly, protein content of ETC complexes I, II, and IV was significantly greater in OT compared with both YG and OG (p &amp;lt; .001). Protein content of peroxisome proliferator-activated receptor gamma, coactivator 1 α (PGC-1α), was greater in OT compared with YG and OG (p &amp;lt; .001). Our results suggest that the aging process per se is not associated with a decline in gene expression and protein content of ETC complexes. Mitochondrial-related gene expression and protein content are substantially greater in OT, suggesting that exercise-mediated increases in mitochondrial content can be maintained into later life

Metabolomic and lipidomic plasma profile changes in human participants ascending to Everest Base Camp.

At high altitude oxygen delivery to the tissues is impaired leading to oxygen insufficiency (hypoxia). Acclimatisation requires adjustment to tissue metabolism, the details of which remain incompletely understood. Here, metabolic responses to progressive environmental hypoxia were assessed through metabolomic and lipidomic profiling of human plasma taken from 198 human participants before and during an ascent to Everest Base Camp (5,300 m). Aqueous and lipid fractions of plasma were separated and analysed using proton (1H)-nuclear magnetic resonance spectroscopy and direct infusion mass spectrometry, respectively. Bayesian robust hierarchical regression revealed decreasing isoleucine with ascent alongside increasing lactate and decreasing glucose, which may point towards increased glycolytic rate. Changes in the lipid profile with ascent included a decrease in triglycerides (48-50 carbons) associated with de novo lipogenesis, alongside increases in circulating levels of the most abundant free fatty acids (palmitic, linoleic and oleic acids). Together, this may be indicative of fat store mobilisation. This study provides the first broad metabolomic account of progressive exposure to environmental hypobaric hypoxia in healthy humans. Decreased isoleucine is of particular interest as a potential contributor to muscle catabolism observed with exposure to hypoxia at altitude. Substantial changes in lipid metabolism may represent important metabolic responses to sub-acute exposure to environmental hypoxia.King's College London, National Institute of Health Researc

Effects of low frequency electrical stimulation training on muscle contractile properties of paralysed muscle: preliminary results

INTRODUCTION It is known from animal studies that muscle composition can be altered in response to different patterns of usage or stimulus (2). However, in man the effects of different types of training on muscle fibre type composition have not achieved a common agreement. This is partly due to the difficulty in controlling the stimuli the muscle receives because the training stimuli can only be superimposed on the daily activities usually undertaken. The muscles of spinal cord injured individuals provide a unique model for studying the process and mechanism of specific training effect, since these muscles are in a highly detrained state containing a low proportion of type I fibres/myosin heavy chain (MHC)-I isoforms (1,3,4,5), and because the stimuli received by the muscles can be more closely controlled by the investigators. The purpose of present study was to investigate the effects of chronic low frequency electrical stimulation training on the contractile properties and muscle composition of the tibialis anterior muscle in a group of spinal cord injured individuals. This paper reports the preliminary results of muscle contractile property changes after four weeks of training. METHODS Five male paraplegic subjects, aged 29 to 48 years, with 5 to 12 years post spinal cord injury, gave their consent to participate in the study which was approved by the local ethical committee. The subjects were trained in the laboratory under supervision, five days a week for four weeks. The training was carried out on a custom build device that held the leg in a position of knee joint angle of 90deg and ankle joint angle of 10deg of plantar flexion. A rigid foot piece was applied on the dorsum of the foot to restrict any movement of the foot and toes, and to provide a resistance to dorsiflexion when the anterior tibialis muscle was stimulated. Percutaneous electrical stimulation was provided by a Uni-Tens 2031 Stimulator (ASAH medico, Denmark), with the stimulation electrodes placed over the motor point area of the muscle. Surface EMG electrodes were placed on the muscle belly to record M-waves. Force responses were monitored using a sensitive strain gauge force transducer attached to a analogue-to-digital converter. The training stimulation frequency was 10 Hz, with a duty cycle of 5 s on and 5 s off, and a pulse width of 350 us and current of 60 to 75 mA. This intensity was equivalent to approximately 60-70% of the muscle’s maximal tension at this stimulation frequency. The daily training time started from 1.5-2 hours in the first week and increased gradually till 5-6 hours were performed in the last training week. In each training day, a recovery period of 15-25 min was inserted between stimulation sessions of 30-90 min. Muscle contractile properties of both right (training) and left (control) legs were measured before and after the four weeks of training. The functional tests included single twitches, tetanic contractions evoked at 10, 20, 50 and 100 Hz, and a fatigue test where the muscle was stimulated at 20 Hz for 2 s with 3 s recovery for 5 min. The major parameters analysed included peak torque (Pt), time to peak torque (TPT), half-relaxation time (1/2RT), fatigue index (FI), and electromechanical delay (EMD). Muscle biopsy samples were obtained before and after the training to analyse MHC composition. Student t-test (paired) was used to detect any significant changes between the mean values pre and post training and between the legs. RESULTS All five subjects successfully completed the training program. The average training time during the four weeks was 68.2 (SD 9.1) hours. No significant differences in the functional tests were found between the control and training legs before training. After the training, the trained leg showed significantly increased TPT and decreased FI (both p\u3c0.05) compared with that of pre-training values. The trained leg also showed an elongated EMD and decreased FI compared with the control leg (both p\u3c0.05). The relative changes of the parameters (post compared with pre-training) are shown in the Figure 1. DISCUSSION The training stimulation in the present study was given at a lower frequency (1,5) and for a longer time period (3,4) than that in some other similar studies. The trend of muscle contractile property changes due to the low frequency training was as one might expect from similar studies on animal muscles, notably the increased TPT and resistance to fatigue. Further evidence of a ‘slowing’ in muscle properties is provided by the increase in EMD. These contractile changes were, however, not coupled to any significant increase in torque production evoked tetanically, indicating no change in muscle size, despite the loading applied to the muscle during training. A tendency towards an increase in torque at 10 Hz was observed which may also be indicative of a slower muscle requiring a lower fusion frequency. The changes in MHC composition, muscle fibre cross sectional area, and metabolic characteristics due to the training are under analysis. REFERENCES (1) Martin T.P. , Stein R.B., Hoeppner P.H. & Reid D.C. (1992). J. Appl. Physiol. 72(4): 1401-1406. (2) Pette D. and Vrbova G. (1992). Rev. Physiol. Biochem. Pharm. 120: 115-202. (3) Rochester L., Barron M.J., Chandler C.S., Sutton R.A., Miller S., Johnson M.A. (1995). Paraplegia. 33(9): 514-522. (4) Rochester L., Chandler C.S., Johnson M.A., Sutton R.A. & Miller S. (1995). Paraplegia. 33(8): 437-449. (5) Stein R.B., Gordon T., Jefferson J., Sharfenberger A., Yang J.F., Totosy De Zepetnek J. & Belanger M. (1992). J. Appl. Physiol. 72(4): 1393-1400