Mitochondrial Adaptations in Elderly and Young Men Skeletal Muscle Following 2 Weeks of Bed Rest and Rehabilitation

The aim of the study was to evaluate the expression levels of proteins related to mitochondrial biogenesis regulation and bioenergetics in vastus lateralis muscle biopsies from 16 elderly and 7 young people subjected to 14 days of bed-rest, causing atrophy, and subsequent 14 days of exercise training. Based on quantitative immunoblot analyses, in both groups a reduction of two key regulators of mitochondrial biogenesis/remodeling and activity, namely PGC-1alpha and Sirt3, was revealed during bedrest,with a subsequent up-regulation after rehabilitation, indicating an involvement of PGC-1alpha-Sirt3 axis in response to the treatments. A difference was observed comparing the young and elderly subjects as, for both proteins, the abundance in the elderly was more affected by immobility and less responsive to exercise. The expression levels of TOM20 and Citrate Synthase, assayed as markers of outer mitochondrial membrane and mitochondrial mass, showed a noticeable sensitivity in the elderly group, where they were affected by bed-rest and rehabilitation recalling the pattern of PGC-1alpha. TOM20 and CS remained unchanged in young subjects. Single OXPHOScomplexes showed peculiar patterns, which were in some cases dissimilar from PGC 1alpha, and suggest different influences on protein biogenesis and degradation. Overall,exercise was capable to counteract the effect of immobility, when present, except for complex V, which was markedly downregulated by bed-rest, but remained unaffected after rehabilitation, maybe as result of greater extent of degradation processes over biogenesis. Phosphorylation extent of AMPK, and its upstream activator LKB1, did not change after bed-rest and rehabilitation in either young or elderly subjects, suggestingthat the activation of energy-sensing LKB1-AMPK signaling pathway was \u201cmissed\u201d due to its transient nature, or was not triggered under our conditions. Our study demonstrates that, as far as the expression of various proteins related to mitochondrial biogenesis/remodeling, adaptations to bed-rest and rehabilitation in the two populations were different. The impact of bed-rest was greater in the elderly subjects, where the pattern (decrease after bed rest and recovery following rehabilitation) was accompanied by changes of mitochondrial mass. Modifications of protein abundance were matched with data obtained from gene expression analyses of four public human datasets focusing on related genes

Galanin and Adrenomedullin Plasma Responses During Artificial Gravity on a Human Short-Arm Centrifuge

Galanin and adrenomedullin plasma responses to head-up tilt and lower body negative pressure have been studied previously. However, to what extent short-arm human centrifugation (SAHC) affects these responses is not known. In this study, we assessed how the application of variable gradients of accelerations (ΔGz) via shifting of the rotation axis during centrifugation affects selected hormonal responses. Specifically, we tested the hypothesis, that cardiovascular modulating hormones such as galanin and adrenomedullin will be higher in non-finishers (participants in whom at least one of the pre-defined criteria for presyncope was fulfilled) when compared to finishers (participants who completed the entire protocol in both sessions) during SAHC exposure. Twenty healthy subjects (10 women and 10 men) were exposed to two g-levels [1 Gz and 2.4 Gz at the feet (Gz_Feet)] in two positions (axis of rotation placed above the head and axis of rotation placed at the heart level). Elevated baseline levels of galanin appeared to predict orthostatic tolerance (p = 0.054) and seemed to support good orthostatic tolerance during 1 Gz_Feet SAHC (p = 0.034). In finishers, 2.4 Gz_Feet SAHC was associated with increased galanin levels after centrifugation (p = 0.007). For adrenomedullin, the hypothesized increases were observed after centrifugation at 1 Gz_Feet (p = 0.031), but not at 2.4 Gz_Feet, suggesting that other central mechanisms than local distribution of adrenomedullin predominate when coping with central hypovolemia induced by SAHC (p > 0.14). In conclusion, baseline galanin levels could potentially be used to predict development of presyncope in subjects. Furthermore, galanin levels increase during elevated levels of central hypovolemia and galanin responses appear to be important for coping with such challenges. Adrenomedullin release depends on degree of central hypovolemia induced fluid shifts and a subject’s ability to cope with such challenges. Our results suggest that the gradient of acceleration (ΔGz) is an innovative approach to quantify the grade of central hypovolemia and to assess neurohormonal responses in those that can tolerate (finishers) or not tolerate (non-finishers) artificial gravity (AG). As AG is being considered as a preventing tool for spaceflight induced deconditioning in future missions, understanding effects of AG on hormonal responses in subjects who develop presyncope is important

Mitochondrial Adaptations in Elderly and Young Men Skeletal Muscle Following 2 Weeks of Bed Rest and Rehabilitation

The aim of the study was to evaluate the expression levels of proteins related to mitochondrial biogenesis regulation and bioenergetics in vastus lateralis muscle biopsies from 16 elderly and 7 young people subjected to 14 days of bed-rest, causing atrophy, and subsequent 14 days of exercise training. Based on quantitative immunoblot analyses, in both groups a reduction of two key regulators of mitochondrial biogenesis/remodeling and activity, namely PGC-1α and Sirt3, was revealed during bed-rest, with a subsequent up-regulation after rehabilitation, indicating an involvement of PGC-1α-Sirt3 axis in response to the treatments. A difference was observed comparing the young and elderly subjects as, for both proteins, the abundance in the elderly was more affected by immobility and less responsive to exercise. The expression levels of TOM20 and Citrate Synthase, assayed as markers of outer mitochondrial membrane and mitochondrial mass, showed a noticeable sensitivity in the elderly group, where they were affected by bed-rest and rehabilitation recalling the pattern of PGC-1α. TOM20 and CS remained unchanged in young subjects. Single OXPHOS complexes showed peculiar patterns, which were in some cases dissimilar from PGC-1α, and suggest different influences on protein biogenesis and degradation. Overall, exercise was capable to counteract the effect of immobility, when present, except for complex V, which was markedly downregulated by bed-rest, but remained unaffected after rehabilitation, maybe as result of greater extent of degradation processes over biogenesis. Phosphorylation extent of AMPK, and its upstream activator LKB1, did not change after bed-rest and rehabilitation in either young or elderly subjects, suggesting that the activation of energy-sensing LKB1-AMPK signaling pathway was “missed” due to its transient nature, or was not triggered under our conditions. Our study demonstrates that, as far as the expression of various proteins related to mitochondrial biogenesis/remodeling, adaptations to bed-rest and rehabilitation in the two populations were different. The impact of bed-rest was greater in the elderly subjects, where the pattern (decrease after bed rest and recovery following rehabilitation) was accompanied by changes of mitochondrial mass. Modifications of protein abundance were matched with data obtained from gene expression analyses of four public human datasets focusing on related genes

Skeletal muscle oxidative function in vivo and ex vivo in athletes with marked hypertrophy from resistance training

Oxidative function during exercise was evaluated in 11 young athletes with marked skeletal muscle hypertrophy induced by long-term resistance training (RTA, body mass 102.67.3 kg, meanSD) and 11 controls (CTRL, body mass 77.86.0). Pulmonary O2 uptake (V\u27O2) and vastus lateralis muscle fractional O2 extraction (by near-infrared spectroscopy) were determined during an incremental cycle ergometer (CE) and one-leg knee-extension (KE) exercise. Mitochondrial respiration was evaluated ex vivo by high-resolution respirometry in permeabilized vastus lateralis fibers obtained by biopsy. Quadriceps femoris muscle cross sectional area, volume (determined by magnetic resonance imaging) and strength were greater in RTA vs. CTRL (by ~40%, ~33% and ~20%, respectively). V\u27O2peak during CE was higher in RTA vs. CTRL (4.050.64 L min-1 vs. 3.560.30)no difference between groups was observed during KE. The O2 cost of CE exercise was not different between groups. When divided per muscle mass (for CE) or quadriceps muscle mass (for KE) V\u27O2peak was lower (by 15-20%) in RTA vs. CTRL. Vastus lateralis fractional O2 extraction was lower in RTA vs. CTRL at all work rates, both during CE and KE. RTA had higher ADP-stimulated mitochondrial respiration (56.723.7 pmolO2s-1mg-1 ww) vs. CTRL (35.710.2), and a tighter coupling of oxidative phosphorylation. In RTA the greater muscle mass and maximal force, and the enhanced mitochondrial respiration seem to compensate for the hypertrophy-induced impaired peripheral O2 diffusion. The net results are an enhanced whole body oxidative function at peak exercise, and unchanged efficiency and O2 cost at submaximal exercise, despite a much greater body mas

Maximal oxygen uptake and fatty acid oxidation in athletic older men and women and healthy control

Introduction: Cardiopulmonary and musculoskeletal systems deteriorate through middle and into older age. This has a negative impact on physical capability and energy metabolism. The purpose of the present study was to determine the effects of ageing and exercise on peak rates of oxygen uptake (VO2peak) and fatty acid oxidation (PFO).Methods: All participants provided written, informed consent. Masters Athletes (MA: n=40, aged 37-90) specialised in endurance (n=10) or sprint running (n=30) were recruited during the 2012 European MA Championships in Zittau, Germany. Untrained (n=42, aged 18-67; 23 men and 16 women) were recruited from the general Manchester population (UK). The untrained participants also completed 12 weeks very high intensity sprint cycle training (4* 20s at 170% VO2max, 3/wk). VO2max and PFO were assessed using indirect calorimetry and incremental cycle ergometry. Statistical significance was gained by independent samples t-tests using IBM SPSS v.20.Results: The endurance and sprint trained MA were a similar age and had similar VO2max (Endurance MA: 47.22 ml/kg/min (±4.15) vs Sprint MA: 43.52 ml/kg/min (±2.21) p=0.416). Both MA groups were significantly higher than untrained people (38.86 ml/kg/min). MA sprinters and endurance runners had a VO2max similar to 19 years younger untrained, healthy people. Regression analysis showed that VO2max decreased by around 11% per decade after the age of 40 yrs in the MA group and 5% per decade after the age of 40 yrs in the untrained group. PFO was similar in endurance and sprint trained MA (Endurance: 8.09 mg/kg/min (±0.95) vs Sprint: 6.91 mg/kg/min (±0.53) p=0.284). In the untrained group, PFO was significantly lower than MA (p=0.006). Regression showed that PFO of MAs was similar to that of an untrained, healthy person 19 years younger. The sprint-training programme caused VO2max to increase by 10% (Pre: 38.86 ml/kg/min (±1.31) vs Post: 42.84 ml/kg/min (±1.24) p<0.001) and PFO to increase by 18% (Pre: 5.57 mg/kg/min (±0.33) vs Post: 6.58 mg/kg/min (±0.41) p=0.050).Conclusion: These results show that MAs have a cardiopulmonary and metabolic fitness at levels equivalent to someone almost 20 yrs younger. Previously untrained middle-aged people can achieve substantial gains in fitness by completing relatively short duration, but high intensity sprint training and reach levels similar to those observed in the master athletes

Bone adaptation to altered loading after spinal cord injury: a study of bone and muscle strength

Bone loss from the paralysed limbs after spinal cord injury (SCI) is well documented. Under physiological conditions, bones are adapted to forces which mainly emerge from muscle pull. After spinal cord injury (SCI), muscles can no longer contract voluntarily and are merely activated during spasms. Based on the Ashworth scale, previous research has suggested that these spasms may mitigate bone losses. We therefore wished to assess muscle forces after SCI with a more direct measure and compare it to measures of bone strength. We hypothesized that the bones in SCI patients would be in relation to the loss of muscle forces. Six male patients with SCI 6.4 (SD 4.3) years earlier and 6 age-matched, able-bodied control subjects were investigated. Bone scans from the right knee were obtained by pQCT. The knee extensor muscles were electrically stimulated via the femoral nerve, isometric knee extension torque was measured and patellar tendon force was estimated. Tendon force upon electrical stimulation in the SCI group was 75% lower than in the control subjects (p<0.01). Volumetric bone mineral density of the patella and of the proximal tibia epiphysis were 50% lower in the SCI group than in the control subjects (p<0.01). Cortical area was lower by 43% in the SCI patients at the proximal tibia metaphysis, and by 33% at the distal femur metaphysis. No group differences were found in volumetric cortical density. Close curvilinear relationships were found between stress and volumetric density for the tibia epiphysis (r(2)=0.90) and for the patella (r(2)=0.91). A weaker correlation with the tendon force was found for the cortical area of the proximal tibia metaphysis (r(2)=0.63), and none for the distal femur metaphysis. These data suggest that, under steady state conditions after SCI, epiphyseal bones are well adapted to the muscular forces. For the metaphysis of the long bones, such an adaptation appears to be less evident. The reason for this remains unclear

Fibula: The Forgotten Bone-May It Provide Some Insight On a Wider Scope for Bone Mechanostat Control?

The human fibula responds to its mechanical environment differently from the tibia accordingly with foot usage. Fibula structure is unaffected by disuse, and is stronger concerning lateral bending in soccer players (who evert and rotate the foot) and weaker in long-distance runners (who jump while running) with respect to untrained controls, along the insertion region of peroneus muscles. These features, strikingly associated to the abilities of the fibulae of predator and prey quadrupeds to manage uneven surfaces and to store elastic energy to jump, respectively, suggest that bone mechanostat would control bone properties with high selective connotations beyond structural strength

Adenosine/A2B receptor signaling ameliorates the effects of ageing and counteracts obesity

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti-obesity potential

Effects of submaximal activation on the determinants of power of chemically skinned rat soleus fibres

Reducing the activating calcium concentration with skinned fibres is known to decrease isometric force and maximal shortening velocity, both of which will reduce the peak power. However, power is also a function of the curvature of the force-velocity relationship, and there is limited information on how changes in activating calcium affect this important property of muscle fibres. Force-velocity relationships of permeabilized single type I fibres from rat soleus muscle were determined using isotonic contractions at 15°C with both maximal (pCa 4.5) and submaximal activation (pCa 5.6). The rate of tension redevelopment (k(tr)), which provides a measure of sum of the apparent rate constants for cross-bridge attachment and detachment (f(app) + g(app)) following a rapid release and restretch, was also measured. Compared with pCa 4.5, specific tension (P(o)) at pCa 5.6 declined by 22 ± 8% (mean ± s.d.) and the maximal velocity of shortening (V(max)) fell by 44 ± 7%, but curvature of the force-velocity relationship (a/P(o)) rose by 47 ± 31%, indicating a less concave relationship. The value of k(tr) declined by 23 ± 7%. The change in a/P(o) reduced the impact of changes in P(o) and V(max) on peak power by approximately 25%. Fitting the data to Huxley's model of cross-bridge action suggests that lower activating calcium decreased both the rate constant for cross-bridge attachment (f) and that for detachment of negatively strained cross-bridges (g(2)). The fact that V(max) (and thus g(2)) changed to a greater extent than k(tr) (f(app) + g(app)) is the reason that reduced activation results in a reduction in curvature of the force-velocity relationship