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Vibration mechanosignals superimposed to resistive exercise result in baseline skeletal muscle transcriptome profiles following chronic disuse in bed rest.

ABSTRACT: Disuse-induced muscle atrophy is a major concern in aging, in neuromuscular diseases, post-traumatic injury and in microgravity life sciences affecting health and fitness also of crew members in spaceflight. By using a laboratory analogue to body unloading we perform for the first time global gene expression profiling joined to specific proteomic analysis to map molecular adaptations in disused (60 days of bed rest) human soleus muscle (CTR) and in response to a resistive exercise (RE) countermeasure protocol without and with superimposed vibration mechanosignals (RVE). Adopting Affymetrix GeneChip technology we identified 235 differently transcribed genes in the CTR group (end- vs. pre-bed rest). RE comprised 206 differentially expressed genes, whereas only 51 changed gene transcripts were found in RVE. Most gene transcription and proteomic changes were linked to various key metabolic pathways (glycolysis, oxidative phosphorylation, tricarboxylic acid (TCA) cycle, lipid metabolism) and to functional contractile structures. Gene expression profiling in bed rest identified a novel set of genes explicitly responsive to vibration mechanosignals in human soleus. This new finding highlights the efficacy of RVE protocol in reducing key signs of disuse maladaptation and atrophy, and to maintain a close-to-normal skeletal muscle quality outcome following chronic disuse in bed rest.

SUBMITTER: Salanova M

PROVIDER: S-EPMC4657004 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Vibration mechanosignals superimposed to resistive exercise result in baseline skeletal muscle transcriptome profiles following chronic disuse in bed rest.

Salanova Michele M Gambara Guido G Moriggi Manuela M Vasso Michele M Ungethuem Ute U Belavý Daniel L DL Felsenberg Dieter D Cerretelli Paolo P Gelfi Cecilia C Blottner Dieter D

Scientific reports 20151124

Disuse-induced muscle atrophy is a major concern in aging, in neuromuscular diseases, post-traumatic injury and in microgravity life sciences affecting health and fitness also of crew members in spaceflight. By using a laboratory analogue to body unloading we perform for the first time global gene expression profiling joined to specific proteomic analysis to map molecular adaptations in disused (60 days of bed rest) human soleus muscle (CTR) and in response to a resistive exercise (RE) counterme ...[more]

PMID: 26596638

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Project description:Current inflight countermeasures do not completely prevent bone and cardiovascular changes induced by microgravity. High load Resistance Exercise combined with whole body Vibration (RVE) demonstrated benefits on bone and cardiovascular system during previous Head-Down Bed Rest (HDBR) studies. We examined the effectiveness of RVE alone or combined with a nutritional supplementation of Whey protein (NeX) on cardiovascular deconditioning. Eight male subjects (age 34 ± 8 years) in a crossover design completed three 21-day HDBR campaigns (Control-CON, RVE, and NeX). Pre and post HDBR Orthostatic Tolerance (OT) was evaluated by a 15-min head-up tilt test followed by increasing levels of Lower Body Negative Pressure (LBNP). Heart rate (HR), blood pressure (BP), and Sympathetic Index (?I) through spectral analysis were measured during OT test. Plasma Volume (PV), and Maximal Oxygen Uptake (VO2max) were measured before and after each campaign. Left ventricular mass, left ventricular end diastolic (LVEDV), end systolic (LVESV), stroke (SV) volumes, and circumferential deformation at rest and during an orthostatic stress simulated by a 30 mmHg LBNP were measured by cardiac MRI. RVE failed to prevent any change in these variables and NeX did not have any additional effect over exercise alone. In the 3 groups, (1) OT time dropped similarly (bed rest p < 0.001), (2) HR and ?I were increased at rest at the end of HDBR and HR increased markedly during LBNP-tilt test, with inability to increase further the ?I, (3) PV dropped (bed rest p < 0.001), along with LVEDV, LVESV and SV (p = 0.08, p < 0.001, and p = 0.045, respectively), (4) Left ventricle mass did not change significantly, (5) Deformation of the heart assessed by global circumferential strain was preserved and early diastolic circumferential strain rate was increased during orthostatic stress at the end of HDBR, illustrating preserved systolic and diastolic function respectively, without any difference between groups. Despite the drop in PV and LV volumes, RVE and NeX tended to alleviate the decrease in VO2max. In conclusion, RVE and NeX failed to prevent the cardiovascular deconditioning induced by a 21 day-HDBR.

Project description:ObjectivesThe time course and magnitude of atrophic remodeling and the effects of an acute rehabilitation program on muscle atrophy are unclear. We sought to characterize bed rest-induced leg muscle atrophy and evaluate the safety and efficacy of an acute rehabilitation program.DesignPrespecified analysis of a randomized controlled trial.SettingSingle-center urban hospital.PatientsAdults (24-55 yr) randomized to 70 days of sedentary bed rest.InterventionsThe 11-day post-bed rest rehabilitation program consisted of low intensity exercise and progressed to increased aerobic exercise duration, plyometric exercises, and higher intensity resistance exercise.Measurements and main resultsUpper (rectus femoris, vastus lateralis, quadriceps, hamstrings, adductors) and lower leg (medial gastrocnemius, lateral gastrocnemius, and soleus) MRI scans were obtained once before, nine times during, and three times after bed rest to assess muscle cross-sectional area. The magnitude and rate of muscle atrophy and recovery were determined for each muscle. Nine participants completed 70 days of sedentary bed rest and an 11-day rehabilitation program. A total of 11,588 muscle cross-sectional area images were quantified. Across all muscles except the rectus femoris (no change), there was a linear decline during bed rest, with the highest atrophic rate occurring in the soleus (-0.33%/d). Following rehabilitation, there was rapid recovery in all muscles; however, the quadriceps (-3.74 cm2; 95% CI, -7.36 to -0.12; p = 0.04), hamstrings (-2.30 cm2; 95% CI, -4.07 to -0.54; p = 0.01), medial gastrocnemius (-0.62 cm2; 95% CI, -1.10 to -0.14; p = 0.01), and soleus (-1.85 cm2; 95% CI, -2.90 to -0.81; p < 0.01) remained significantly lower than baseline.ConclusionsBed rest results in upper and lower leg muscle atrophy in a linear pattern, and an 11-day rehabilitation program was safe and effective in initiating a rapid trajectory of muscle recovery. These findings provide important information regarding the design and refinement of rehabilitation programs following bed rest.

Project description:The pro- and anti-inflammatory macrophages are associated with insulin sensitivity and skeletal muscle regeneration. Infiltrating macrophages in skeletal muscle during a period of physical inactivity and subsequent reloading/rehabilitation in older adults is unknown, but may provide insight into mechanisms related to the development of metabolic disease and changes in muscle cell size. The purpose of this study was to determine if skeletal muscle macrophage infiltration is modulated differently between young and older adults after bed rest and exercise rehabilitation and if these responses are related to muscle and insulin sensitivity changes. 14 young and 9 older adults underwent 5-days of bed rest followed by 8-weeks of lower limb eccentric exercise rehabilitation (REHAB). Dual-energy X-ray absorptiometry, magnetic resonance imaging and myofiber analysis were used to identify muscle morphology and CLIX-IR and CLIX-β were used to assess insulin sensitivity. Skeletal muscle macrophages, CD68 (pan), CD11b (M1), CD163 (M2), CD206 (M2), were characterized using immunohistochemistry and gene expression. Insulin sensitivity, independent of age, decreased ~38% following bed rest and was restored following REHAB. We found robust age-related differences in muscle atrophy during bed rest, yet older and younger adults equally hypertrophied during REHAB. Interestingly, there were age-related differences in macrophage content (CD68+CD11b+ and CD68+CD11b- cells) but both young and old similarly increased macrophages with REHAB. Satellite cell changes during rehab corresponded to macrophage content changes. Muscle tissue resident macrophages and gene expression, were not associated with changes in insulin sensitivity following bed rest and REHAB. These data suggest that muscle macrophages are modulated as a result of exercise rehabilitation following bed rest and may more associated with muscle regrowth/hypertrophy rather than insulin sensitivity in young or older adults. This trial was registered at clinicaltrials.gov as NCT01669590.

Project description:Microgravity has a dramatic impact on human physiology, illustrated in particular with skeletal muscle impairment. A thorough understanding of the mechanisms leading to loss of muscle mass and structural disorders is necessary for the definition of efficient clinical and spaceflight countermeasures. We investigated the effects of long-term bed rest on transcriptome of soleus (SOL) and vastus lateralis (VL) muscles in healthy women (BRC group, n=8), and the potential beneficial impact of protein supplementation (BRN group, n=8) and of a combined resistance and aerobic training (BRE group, n=8). Gene expression profiles were obtained using an in-house made microarray containing 6681 muscles-relevant genes. A two-class statistical analysis was applied on the 2103 genes with consolidated expression. We identified 472 and 207 modified genes, respectively for SOL and VL in BRC group. Further clustering approaches, identifying relevant biological mechanisms or pathways, underlined five main subclusters. Three are composed almost of upregulated genes involved mainly in nucleic acid and protein metabolism, and two composed almost of downregulated genes involved in energy metabolism. Exercise countermeasure demonstrated a drastic compensatory effect, decreasing the number of differentially-expressed genes by 89 and 96% in SOL and VL. In contrast, nutrition countermeasure had a moderate effect and decreased the number of differentially-expressed genes by 40 and 25% in SOL and VL. Our results allowed reporting a systematic, global and comprehensive view of long-term woman muscle atrophy and brought new lights and insights for space environment and for women who undergo a long-term clinical bed rest. Biological samples were collected from Pre- and Post- bed rest (BR) soleus and vastus lateralis biopsies of each subject from the three groups (bed rest only: BRC; Exercise: BRE; Nutrition: BRN). six technical replicate values (2 duplicate hybridizations âa et bâ to chips with triplicate spots âxxxâ) were obtained for each skeletal muscle sample. Thus for each subject, 12 expression measurements (6 before BR and 6 after BR) were obtained for each muscle.

Project description:Short-term muscle disuse induces significant muscle loss in older adults and in some reports may be more accelerated with aging. Identifying muscle transcriptional events in response to bed rest may help identify therapeutic targets to offset muscle loss. Therefore, we compared the muscle transcriptome between young and older adults after bed rest and identified candidate targets related to changes in muscle loss. RNA was sequenced (HiSeq, Illumina; DESeq, R) from muscle biopsies obtained from young [ n = 9; 23 yr (SD 3)] and older [ n = 18; 68 yr (SD 6)] adults before and after 5-day bed rest. Significantly altered pathways in both young and old subjects relating to mechanosensing and cell adhesion (Actin Cytoskeleton Signaling, ILK Signaling, RhoA Signaling, and Integrin Signaling) were altered (activation z score) to a greater extent in old subjects. Hepatic Fibrosis/Hepatic Stellate Cell Activation was the top regulated pathway significantly altered only in the old. Fifty-one differentially regulated genes were only altered in the young after bed rest and resembled a gene expression profile like that in the old at baseline. Inflammation and muscle wasting genes (CXCL2, GADD45A) were uniquely increased in the old after bed rest, and the macrophage gene MAFB decreased in the old and correlated with the change in leg lean mass. In summary, skeletal muscle dysregulation during bed rest in the old may be driven by alterations in molecules related to fibrosis, inflammation, and cell adhesion. This information may aid in the development of mechanistic-based therapies to combat muscle atrophy during short-term disuse. NEW & NOTEWORTHY Using RNA sequencing and bioinformatics approaches, we identified that older adult skeletal muscle was characterized by dysregulated pathways associated with fibrosis, inflammation (upregulated), and cell adhesion and mechanosensing (downregulated) pathways, with a subset of genes differentially regulated in old and young muscle after bed rest that may describe predisposition to muscle loss. Unique upregulated genes only expressed in old muscle after bed rest indicated increased inflammation and muscle wasting (CXCL2, GADD45A) and decreased MAFB correlated with the change in leg lean mass.

Dataset Information

Vibration mechanosignals superimposed to resistive exercise result in baseline skeletal muscle transcriptome profiles following chronic disuse in bed rest.

Publications

Vibration mechanosignals superimposed to resistive exercise result in baseline skeletal muscle transcriptome profiles following chronic disuse in bed rest.

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