Genetic variants associated with exercise performance in both moderately trained and highly trained individuals.

Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study; n = 58 and Hawaiian Ironman Triathlon 2008; n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO2 max) in recreationally active individuals and a triathlon time-to-completion (Hawaiian Ironman Triathlon cohort only). A nominal significance threshold of α < 0.05 was used to identify 17 variants (11 in the Gene SMART population and six in the Hawaiian Ironman Triathlon cohort) which were significantly associated with performance gains in highly trained individuals. The variant rs1474347 located in Interleukin 6 (IL6) was the only variant with a false discovery rate < 0.05 and was found to be associated with gains in VO2 max (additional 4.016 mL/(kg min) for each G allele inherited) after training in the Gene SMART cohort. In summary, this study found further evidence to suggest that genetic variance can influence training response in a moderately trained cohort and provides an example of the potential application of genomic research in the assessment of exercise trait response.

Coupling of myocardial stress resistance and signalling to voluntary activity and inactivity.

AIMS: We examined coupling of myocardial ischaemic tolerance to physical activity and inactivity, and whether this involves modulation of survival (AKT, AMPK, ERK1/2, HSP27, EGFR) and injury (GSK3ß) proteins implicated in ischaemic preconditioning and calorie restriction. METHODS: Proteomic modifications were assessed in ventricular myocardium, and tolerance to 25-min ischaemia in ex vivo perfused hearts from C57Bl/6 mice subjected to 14-day voluntary activity in running-naïve animals (Active); 7 days of subsequent inactivity (Inactive); brief (day 3) restoration of running (Re-Active); or time-matched inactivity. RESULTS: Active mice increased running speed and distance by 75-150% over 14 days (to ~40 m min(-1) and 10 km day(-1) ), with Active hearts resistant to post-ischaemic dysfunction (40-50% improvements in ventricular pressure development, diastolic pressure and dP/dt). Cardioprotection was accompanied by ~twofold elevations in AKT, AMPK, HSP27 and GSK3ß phosphorylation and EGFR expression. Ischaemic tolerance was reversed in Inactive hearts, paralleling reduced EGFR expression and GSK3ß and ERK1/2 phosphorylation (AKT, AMPK, HSP27 phosphorylation unaltered). Running characteristics, ischaemic tolerance, EGFR expression and GSK3ß phosphorylation returned to Active levels within 1-3 days of restored activity (without changes in AKT, AMPK or HSP27 phosphorylation). Transcriptional responses included activity-dependent Anp induction vs. Hmox1 and Sirt3 suppression, and inactivity-dependent Adora2b induction. CONCLUSIONS: Data confirm the sensitive coupling of ischaemic tolerance to activity: voluntary running induces cardioprotection that dissipates within 1 week of inactivity yet recovers rapidly upon subsequent activity. While exercise in naïve animals induces a molecular profile characteristic of preconditioning/calorie restriction, only GSK3ß and EGFR modulation consistently parallel activity- and inactivity-dependent ischaemic tolerance.

The impact of an experimentally induced increase in arterial blood pressure on left ventricular twist mechanics.

The effects of isometric hand-grip exercise (IHG) coupled with a period of postexercise circulatory occlusion (OCC; known to sustain exercise-induced increases in blood pressure while facilitating a decrease in heart rate) on left ventricular (LV) twist mechanics was examined. Two-dimensional speckle-tracking echocardiography was used to assess LV apical and basal rotation and LV twist in 19 healthy participants (23 ± 2 years old) at rest, during 3 min of IHG (performed at 40% maximal voluntary contraction) and 3 min of OCC immediately following IHG. The IHG elicited significant (P < 0.001) increases in mean arterial pressure (rest, 91 ± 1 mmHg; IHG, 122 ± 2 mmHg) and heart rate (rest, 65 ± 2 beats min(-1); IHG, 91 ± 4 beats min(-1)). Mean arterial pressure remained elevated during OCC (116 ± 2 mmHg; P < 0.001 versus rest), whereas heart rate returned to resting levels (68 ± 3 beats min(-1); P = 0.159 versus rest). Apical rotation decreased significantly (P < 0.01) by 10 ± 5% during IHG and 21 ± 4% during OCC, whereas basal rotation remained unchanged from rest. Left ventricular twist decreased from rest to IHG (12 ± 5%; P = 0.015) and OCC (21 ± 4%; P = 0.001), whereas a decrease in LV untwist rate was observed only during OCC. An increase in blood pressure generated by IHG, and maintained by a period of OCC, impairs aspects of LV twist mechanics. Postexercise circulatory occlusion isolated the effect of the arterial blood pressure rise (from heart rate), magnifying the impairment of LV twist mechanics when compared with IHG, whilst also negatively impacting LV relaxation. We propose that a protocol using isometric exercise followed by circulatory occlusion provides a method for studying the effects of blood pressure changes on LV twist mechanics.

Short-term training alters the control of mitochondrial respiration rate before maximal oxidative ATP synthesis.

AIM: Short-term exercise training may induce metabolic and performance adaptations before any changes in mitochondrial enzyme potential. However, there has not been a study that has directly assessed changes in mitochondrial oxidative capacity or metabolic control as a consequence of such training in vivo. Therefore, we used (31) P-magnetic resonance spectroscopy ((31) P-MRS) to examine the effect of short-term plantar flexion exercise training on phosphocreatine (PCr) recovery kinetics and the control of respiration rate. METHOD: To this aim, we investigated 12 healthy men, experienced with this exercise modality (TRA), and 7 time-control subjects (TC). RESULTS: After 5 days of training, maximum work rate during incremental plantar flexion exercise was significantly improved (P < 0.01). During the recovery period, the maximal rate of oxidative adenosine triphosphate synthesis (PRE: 28 ± 13 mm min(-1) ; POST: 26 ± 15 mm min(-1) ) and the PCr recovery time constant (PRE: 31 ± 19 s; POST: 29 ± 16) were not significantly altered. In contrast, the Hill coefficient (nH ) describing the co-operativity between respiration rate and ADP was significantly increased in TRA (PRE: nH = 2.7 ± 1.4; POST: nH = 3.4 ± 1.9, P < 0.05). Meanwhile, there were no systematic variations in any of these variables in TC. CONCLUSION: This study reveals that 5 days of training induces rapid adaptation in the allosteric control of respiration rate by ADP before any substantial improvement in muscle oxidative capacity occurs.

Does ultrasound guidance improve the outcomes of arthrocentesis and corticosteroid injection of the knee?

OBJECTIVE: The present randomized controlled trial compared arthrocentesis of the effusive knee followed by corticosteroid injection performed by the conventional anatomic landmark palpation-guided technique to the same procedure performed with ultrasound (US) needle guidance. METHODS: Sixty-four palpably effusive knees were randomized to (i) palpation-guided arthrocentesis with a conventional 20-mL syringe (22 knees), (ii) US-guided arthrocentesis with a 25-mL reciprocating procedure device (RPD) mechanical aspirating syringe (22 knees), or (iii) US-guided arthrocentesis with a 60-mL automatic aspirating syringe (20 knees). The one-needle two-syringe technique was used. Outcome measures included patient pain by the Visual Analogue Scale (VAS) for pain (0-10 cm), the proportion of diagnostic samples, synovial fluid volume yield, complications, and therapeutic outcome at 2 weeks. RESULTS: Sonographic guidance resulted in 48% less procedural pan (VAS; palpation-guided: 5.8 ± 3.0 cm, US-guided: 3.0 ± 2.8 cm, p < 0.001), 183% increased aspirated synovial fluid volumes (palpation-guided: 12 ± 10 mL, US-guided: 34 ± 25 mL, p < 0.0001), and improved outcomes at 2 weeks (VAS; palpation-guided: 2.8 ± 2.4 cm, US-guided: 1.5 ± 1.9 cm, p = 0.034). Outcomes of sonographic guidance with the mechanical syringe and automatic syringe were comparable in all outcome measures. CONCLUSIONS: US-guided arthrocentesis and injection of the knee are superior to anatomic landmark palpation-guided arthrocentesis, resulting in significantly less procedural pain, improved arthrocentesis success, greater synovial fluid yield, more complete joint decompression, and improved clinical outcomes.

Pressure generated by syringes: implications for hydrodissection and injection of dense connective tissue lesions.

OBJECTIVE: Hydrodissection and high-pressure injection are important for the treatment of dense connective tissue lesions including rheumatoid nodules, Dupuytren's contracture, and trigger finger. The present study determined the optimal syringes for high-pressure injection of dense connective tissue lesions. METHODS: Different sizes (1, 3, 5, 10, 20, and 60 mL) of a mechanical syringe (reciprocating procedure device) with a luer-lock fitting were studied. Twenty operators generated maximum pressure with each mechanical syringe size, and pressure was measured in pounds per square inch (psi). Subsequently, 223 dense connective tissue lesions were injected with different sizes of syringes (1, 3, or 10 mL). Outcomes included (i) successful intralesional injection and (ii) clinical response at 2 weeks. RESULTS: Smaller syringes generated significantly more injection pressure than did larger syringes: 1 mL (363 ± 197 psi), 3 mL (177 ± 96 psi), 5 mL (73 ± 40 psi), 10 mL (53 ± 29 psi), 20 mL (32 ± 18 psi), and 60 mL (19 ± 12 psi). Similarly, smaller syringes were superior to larger syringes for intralesional injection success: 10 mL: 34% (15/44) vs. 1 mL: 100% (70/70) (p < 0.001) and 3 mL: 91% (99/109) (p < 0.001). CONCLUSION: Smaller syringes (≤ 3 mL) are superior to larger syringes (≥ 5 mL) for successful hydrodissection and high-pressure intralesional injection of dense connective tissue lesions.

The effects of unilateral muscle fatigue on bilateral physiological tremor.

The aim of this study was to examine the post-exercise effects of fatiguing the wrist extensor muscles of a single arm on postural tremor and muscle activity in both arms. Previous research has shown that, for neurologically normal subjects, the tremor seen within a single limb segment is uncorrelated to that seen contralaterally. However it has been speculated that some bilateral relation does exist, and that the nature of the relation may only become evident under conditions where the neuromuscular system is perturbed. To further investigate this potential bilateral relation, seven healthy subjects were required to adopt a bilateral postural pointing position after exercise-induced fatigue of the wrist extensor muscles of a single arm. Tremor from the forearm, hand and finger segments of each arm, surface EMG activity from extensor digitorum (ED) of each arm, and blood lactate data were collected prior to and after the exercise intervention. The main result was that fatiguing the distal muscles of one arm resulted in a bilateral increase in both the physiological tremor and ED activity. The change in tremor was confined to the index finger with no change in the tremor for the hand or forearm segments of either arm. While three peaks were seen in the frequency profile of the finger tremor, the effects of fatigue were confined to an increase in the peak power of the neurally generated 8-12 Hz tremor component. The contralateral increase in muscle activity was also reflected by a change in the frequency profile of the EMG output, with an increase in the peak power of both muscles following exercise of the wrist extensors of a single arm. The bilateral increases in physiological tremor and EMG activity of ED were only observed during the bilateral pointing task, with no changes in tremor or EMG activity seen for the non-exercised limb during the unilateral exercise protocol. The specificity of the resultant increases in the neurally generated 8-12 Hz component of finger tremor amplitude and EMG activity, coupled with the lack of any changes in tremor for the more proximal arm segments, indicate that these bilateral effects were mediated by an increase in the central neural drive to both limbs. Together this set of results challenges the general assumption of bilateral independence of tremor production, and further illustrate the task dependent nature of exercise-induced fatigue.

Evolving techniques for the investigation of muscle bioenergetics and oxygenation.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are both powerful, non-invasive methodologies and, as such, offer great potential to investigate both human biochemistry and human physiology, and ultimately to contribute significantly to the field of medicine. Consequently there has been much effort devoted to fostering the evolution of these methodologies into distinct and applicable techniques. Here we will highlight several MRI and MRS techniques for the assessment of human biochemistry and physiology that ultimately may provide useful clinical assessments and diagnoses of various muscular and cardiovascular pathologies. Specifically, the evolving techniques that will be discussed are: (1) (1)H MRS of myoglobin to assess the intracellular partial pressure of O(2), (2) (31)P MRS to assess metabolic capacity, and (3) the combination of (31)P chemical shift imaging to assess local metabolic demand (oxygen uptake; .VO(2)) with arterial spin labelling to assess local perfusion (blood flow; .Q), in an effort to characterize the elusive spatial matching of skeletal muscle (.Q/.VO(2)).

Local perfusion and metabolic demand during exercise: a noninvasive MRI method of assessment.

A noninvasive magnetic resonance imaging (MRI) method to assess the distribution of perfusion and metabolic demand (Q/VO(2)) in exercising human skeletal muscle is described. This method combines two MRI techniques that can provide accurate multiple localized measurements of Q/VO(2) during steady-state plantar flexion exercise. The first technique, (31)P chemical shift imaging, permits the acquisition of comparable phosphorus spectra from multiple voxels simultaneously. Because phosphocreatine (PCr) depletion is directly proportional to ATP hydrolysis, its relative depletion can be used as an index of muscle O(2) uptake (VO(2)). The second MRI technique allows the measurement of both spatially and temporally resolved muscle perfusion in vivo by using arterial spin labeling. Promising validity and reliability data are presented for both MRI techniques. Initial results from the combined method provide evidence of a large variation in Q/VO(2), revealing areas of apparent under- and overperfusion for a given metabolic turnover. Analysis of these data in a similar fashion to that employed in the assessment of ventilation-to-perfusion matching in the lungs revealed a similar second moment of the perfusion distribution and PCr distribution on a log scale (log SD(Q) and log SD(PCr)) (0.47). Modeling the effect of variations in log SD(Q) and log SD(PCr) in terms of attainable VO(2), assuming no diffusion limits, indicates that the log SD(Q) and log SD(PCr) would allow only 92% of the target VO(2) to be achieved. This communication documents this novel, noninvasive method for assessing Q/VO(2), and initial data suggest that the mismatch in Q/VO(2) may play a significant role in determining O(2) transport and utilization during exercise.

Noninvasive evaluation of adult onset myopathy from carnitine palmitoyl transferase II deficiency using proton magnetic resonance spectroscopy.

OBJECTIVE: The adult onset metabolic myopathy of carnitine palmitoyl transferase II (CPT II) deficiency is under-recognized, in part due to variable degrees of enzyme deficiency and symptomatology, as well as limitations in means for noninvasive evaluation. We describe a proton magnetic resonance spectroscopy (MRS) technique, using a standard clinical magnetic resonance imaging scanner, to diagnose and help monitor the response to therapy in adult CPT II deficiency. METHODS: A 53-year-old woman presented with a long standing history of diffuse aching and fatigue provoked by high fat intake, fasting, or prolonged exertion. Muscle biopsy revealed myopathic features and a deficiency (33% of control) of CPT II activity with elevated palmitoyl carnitine. Proton MRS of the soleus muscle was performed using a 1.5 Tesla scanner before and during dietary therapy. RESULTS: Proton MRS revealed shortening of the transverse relaxation time (T2), consistent with increased acetylation of the carnitine pool. The symptoms resolved completely by treatment with frequent feedings of a high carbohydrate diet low in long chain fatty acids supplemented with medium chain triglycerides and L-carnitine. Recovery of normal muscle MRS and carnitine T2 relaxation was documented by the third month of therapy. CONCLUSION: Proton MRS is a novel, potentially useful, and readily available adjunct in the diagnosis and therapeutic monitoring of muscle CPT II deficiency.