scholarly journals Skeletal Muscle Energetics and Mitochondrial Function Are Impaired Following 10 Days of Bed Rest in Older Adults

2020 ◽  
Vol 75 (9) ◽  
pp. 1744-1753 ◽  
Author(s):  
Robert A Standley ◽  
Giovanna Distefano ◽  
Michelle B Trevino ◽  
Emily Chen ◽  
Niven R Narain ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Mitochondrial Respiration ◽  
Vastus Lateralis ◽  
Mitochondrial Gene ◽  
Bed Rest ◽  
Primary Objective ◽  
Significant Deterioration ◽  
Muscle Energetics ◽  
Gene Transcripts

Abstract Background Older adults exposed to periods of inactivity during hospitalization, illness, or injury lose muscle mass and strength. This, in turn, predisposes poor recovery of physical function upon reambulation and represents a significant health risk for older adults. Bed rest (BR) results in altered skeletal muscle fuel metabolism and loss of oxidative capacity that have recently been linked to the muscle atrophy program. Our primary objective was to explore the effects of BR on mitochondrial energetics in muscle from older adults. A secondary objective was to examine the effect of β-hydroxy-β-methylbuturate (HMB) supplementation on mitochondrial energetics. Methods We studied 20 older adults before and after a 10-day BR intervention, who consumed a complete oral nutritional supplement (ONS) with HMB (3.0 g/d HMB, n = 11) or without HMB (CON, n = 9). Percutaneous biopsies of the vastus lateralis were obtained to determine mitochondrial respiration and H2O2 emission in permeabilized muscle fibers along with markers of content. RNA sequencing and lipidomics analyses were also conducted. Results We found a significant up-regulation of collagen synthesis and down-regulation of ribosome, oxidative metabolism and mitochondrial gene transcripts following BR in the CON group. Alterations to these gene transcripts were significantly blunted in the HMB group. Mitochondrial respiration and markers of content were both reduced and H2O2 emission was elevated in both groups following BR. Conclusions In summary, 10 days of BR in older adults causes a significant deterioration in mitochondrial energetics, while transcriptomic profiling revealed that some of these negative effects may be attenuated by an ONS containing HMB.

scholarly journals Effects of β-hydroxy-β-methylbutyrate on skeletal muscle mitochondrial content and dynamics, and lipids after 10 days of bed rest in older adults

2017 ◽  
Vol 123 (5) ◽  
pp. 1092-1100 ◽  
Author(s):  
Robert A. Standley ◽  
Giovanna Distefano ◽  
Suzette L. Pereira ◽  
Min Tian ◽  
Owen J. Kelly ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Vastus Lateralis ◽  
Bed Rest ◽  
Disuse Atrophy ◽  
Mitochondrial Content ◽  
Cross Sectional ◽  
Oxphos Complex

Loss of muscle mass during periods of disuse likely has negative health consequences for older adults. We have previously shown that β-hydroxy-β-methylbutyrate (HMB) supplementation during 10 days of strict bed rest (BR) attenuates the loss of lean mass in older adults. To elucidate potential molecular mechanisms of HMB effects on muscle during BR and resistance training rehabilitation (RT), we examined mediators of skeletal muscle mitochondrial dynamics, autophagy and atrophy, and intramyocellular lipids. Nineteen older adults (60–76 yr) completed 10 days BR followed by 8-wk RT rehabilitation. Subjects were randomized to either HMB (3 g/day HMB; n = 11) or control (CON; n = 8) groups. Skeletal muscle cross-sectional area (CSA) was determined by histology from percutaneous vastus lateralis biopsies. We measured protein markers of mitochondrial content [oxidative phosphorylation (OXPHOS)], fusion and fission (MFN2, OPA1, FIS1, and DRP1), autophagy (Beclin1, LC3B, and BNIP3), and atrophy [poly-ubiquinated proteins (poly-ub)] by Western blot. Fatty acid composition of several lipid classes in skeletal muscle was measured by infusion-MS analysis. Poly-ub proteins and OXPHOS complex I increased in both groups following BR ( P < 0.05, main effect for time), and muscle triglyceride content tended to increase following BR in the HMB group ( P = 0.055). RT rehabilitation increased OXPHOS complex II protein ( P < 0.05), and total OXPHOS content tended ( P = 0.0504) to be higher in HMB group. In addition, higher levels of DRP1 and MFN2 were maintained in the HMB group after RT ( P < 0.05). BNIP3 and poly-ub proteins were significantly reduced following rehabilitation in both groups ( P < 0.05). Collectively, these data suggest that HMB influences mitochondrial dynamics and lipid metabolism during disuse atrophy and rehabilitation. NEW & NOTEWORTHY Mitochondrial content and dynamics remained unchanged over 10 days of BR in older adults. HMB stimulated intramuscular lipid storage as triacylglycerol following 10 days of bed rest (BR) and maintained higher mitochondrial OXPHOS content and dynamics during the 8-wk resistance exercise rehabilitation program.

Leucine augments specific skeletal muscle mitochondrial respiratory pathways during recovery following 7 days of physical inactivity in older adults

2021 ◽  
Author(s):  
Emily J. Arentson-Lantz ◽  
Jasmine Mikovic ◽  
Nisha Bhattarai ◽  
Christopher S. Fry ◽  
Séverine Lamon ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Bed Rest ◽  
Metabolic Clearance ◽  
Leucine Supplementation ◽  
Respiratory Capacity ◽  
Antioxidant Defense Systems ◽  
Mitochondrial Respiratory

Leucine supplementation attenuates the loss of skeletal muscle mass and function in older adults during bed rest. We sought to determine if leucine could also preserve and/or restore mitochondrial function and muscle oxidative capacity during periods of disuse and rehabilitation. Healthy older adults (69.1 ± 1.1 years) consumed a structured diet with supplemental leucine (LEU: 0.06 g/ kg body weight/ meal; n=8) or alanine (CON: 0.06 g/ kg body weight/meal; n=8) during 7 days of bed rest and 5 days of inpatient rehabilitation. A 75 g oral glucose tolerance test was performed at baseline (PreBR), after bed rest (PostBR) and rehabilitation (PostRehab) and used to calculate an indicator of insulin sensitivity, metabolic clearance rate. (MCR). Tissue samples from the m. vastus lateralis were collected PreBR, PostBR, and PostRehab to assess mitochondrial respiratory capacity and protein markers of the oxidative phosphorylation and a marker of the antioxidant defense systems. During bed rest, leucine tended to preserve insulin sensitivity (Change in MCR, CON vs. LEU: -3.5 ± 0.82 vs LEU: -0.98 ± 0.88, p=0.054), but had no effect on mitochondrial respiratory capacity (Change in State 3+succinate CON vs. LEU -8.7 ± 6.1 vs. 7.3 ± 4.1 pmol O2/sec/mg tissue, p=0.10) Following rehabilitation, leucine increased ATP-linked respiration (CON vs. LEU: -8.9 ± 6.2 vs. 15.5± 4.4 pmol O2/sec/mg tissue, p=0.0042). While the expression of mitochondrial respiratory and antioxidant proteins was not impacted, leucine supplementation preserved specific pathways of mitochondrial respiration, insulin sensitivity and a marker of oxidative stress during bed rest and rehabilitation.

Effect of 10 Days of Bed Rest on Skeletal Muscle in Healthy Older Adults

JAMA ◽  
2007 ◽  
Vol 297 (16) ◽  
pp. 1769 ◽  
Author(s):  
Patrick Kortebein ◽  
Arny Ferrando ◽  
Juan Lombeida ◽  
Robert Wolfe ◽  
William J. Evans
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Bed Rest ◽  
Healthy Older Adults

scholarly journals Short-term bed rest increases TLR4 and IL-6 expression in skeletal muscle of older adults

2013 ◽  
Vol 305 (3) ◽  
pp. R216-R223 ◽  
Author(s):  
Micah J. Drummond ◽  
Kyle L. Timmerman ◽  
Melissa M. Markofski ◽  
Dillon K. Walker ◽  
Jared M. Dickinson ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Inflammatory Cytokines ◽  
Muscle Biopsy ◽  
Lean Mass ◽  
Bed Rest ◽  
Short Term ◽  
Tlr4 Signaling ◽  
Adult Skeletal Muscle ◽  
Healthy Older Adults

Bed rest induces significant loss of leg lean mass in older adults. Systemic and tissue inflammation also accelerates skeletal muscle loss, but it is unknown whether inflammation is associated to inactivity-induced muscle atrophy in healthy older adults. We determined if short-term bed rest increases toll-like receptor 4 (TLR4) signaling and pro-inflammatory markers in older adult skeletal muscle biopsy samples. Six healthy, older adults underwent seven consecutive days of bed rest. Muscle biopsies (vastus lateralis) were taken after an overnight fast before and at the end of bed rest. Serum cytokine expression was measured before and during bed rest. TLR4 signaling and cytokine mRNAs associated with pro- and anti-inflammation and anabolism were measured in muscle biopsy samples using Western blot analysis and qPCR. Participants lost ∼4% leg lean mass with bed rest. We found that after bed rest, muscle levels of TLR4 protein expression and interleukin-6 (IL-6), nuclear factor-κB1, interleukin-10, and 15 mRNA expression were increased after bed rest ( P < 0.05). Additionally, the cytokines interferon-γ, and macrophage inflammatory protein-1β, were elevated in serum samples following bed rest ( P < 0.05). We conclude that short-term bed rest in older adults modestly increased some pro- and anti-inflammatory cytokines in muscle samples while systemic changes in pro-inflammatory cytokines were mostly absent. Upregulation of TLR4 protein content suggests that bed rest in older adults increases the capacity to mount an exaggerated, and perhaps unnecessary, inflammatory response in the presence of specific TLR4 ligands, e.g., during acute illness.

scholarly journals Quadriceps exercise intolerance in patients with chronic obstructive pulmonary disease: the potential role of altered skeletal muscle mitochondrial respiration

2015 ◽  
Vol 119 (8) ◽  
pp. 882-888 ◽  
Author(s):  
Jayson R. Gifford ◽  
Joel D. Trinity ◽  
Gwenael Layec ◽  
Ryan S. Garten ◽  
Song-Young Park ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Skeletal Muscle ◽  
Pulmonary Disease ◽  
Mitochondrial Respiration ◽  
Exercise Tolerance ◽  
Vastus Lateralis ◽  
Knee Extensor ◽  
Exercise Intolerance ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

This study sought to determine if qualitative alterations in skeletal muscle mitochondrial respiration, associated with decreased mitochondrial efficiency, contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). Using permeabilized muscle fibers from the vastus lateralis of 13 patients with COPD and 12 healthy controls, complex I (CI) and complex II (CII)-driven State 3 mitochondrial respiration were measured separately (State 3:CI and State 3:CII) and in combination (State 3:CI+CII). State 2 respiration was also measured. Exercise tolerance was assessed by knee extensor exercise (KE) time to fatigue. Per milligram of muscle, State 3:CI+CII and State 3:CI were reduced in COPD ( P < 0.05), while State 3:CII and State 2 were not different between groups. To determine if this altered pattern of respiration represented qualitative changes in mitochondrial function, respiration states were examined as percentages of peak respiration (State 3:CI+CII), which revealed altered contributions from State 3:CI (Con 83.7 ± 3.4, COPD 72.1 ± 2.4%Peak, P < 0.05) and State 3:CII (Con 64.9 ± 3.2, COPD 79.5 ± 3.0%Peak, P < 0.05) respiration, but not State 2 respiration in COPD. Importantly, a diminished contribution of CI-driven respiration relative to the metabolically less-efficient CII-driven respiration (CI/CII) was also observed in COPD (Con 1.28 ± 0.09, COPD 0.81 ± 0.05, P < 0.05), which was related to exercise tolerance of the patients ( r = 0.64, P < 0.05). Overall, this study indicates that COPD is associated with qualitative alterations in skeletal muscle mitochondria that affect the contribution of CI and CII-driven respiration, which potentially contributes to the exercise intolerance associated with this disease.

Resistance training affects GLUT-4 content in skeletal muscle of humans after 19 days of head-down bed rest

1999 ◽  
Vol 86 (3) ◽  
pp. 909-914 ◽  
Author(s):  
Izumi Tabata ◽  
Youji Suzuki ◽  
Tetsuo Fukunaga ◽  
Toshiko Yokozeki ◽  
Hiroshi Akima ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Resistance Training ◽  
Membrane Protein ◽  
Vastus Lateralis ◽  
Bed Rest ◽  
Training Group ◽  
Control Group ◽  
Glut 4 ◽  
Before And After ◽  
Voluntary Contractions

This study assessed the effects of inactivity on GLUT-4 content of human skeletal muscle and evaluated resistance training as a countermeasure to inactivity-related changes in GLUT-4 content in skeletal muscle. Nine young men participated in the study. For 19 days, four control subjects remained in a −6° head-down tilt at all times throughout bed rest, except for showering every other day. Five training group subjects also remained at bed rest, except during resistance training once in the morning. The resistance training consisted of 30 isometric maximal voluntary contractions for 3 s each; leg-press exercise was used to recruit the extensor muscles of the ankle, knee, and hip. Pauses (3 s) were allowed between bouts of maximal contraction. Muscle biopsy samples were obtained from the lateral aspect of vastus lateralis (VL) muscle before and after the bed rest. GLUT-4 content in VL muscle of the control group was significantly decreased after bed rest (473 ± 48 vs. 398 ± 66 counts ⋅ min−1 ⋅ μg membrane protein−1, before and after bed rest, respectively), whereas GLUT-4 significantly increased in the training group with bed rest (510 ± 158 vs. 663 ± 189 counts ⋅ min−1 ⋅ μg membrane protein−1, before and after bed rest, respectively). The present study demonstrated that GLUT-4 in VL muscle decreased by ∼16% after 19 days of bed rest, and isometric resistance training during bed rest induced a 30% increase above the value of GLUT-4 before bed rest.

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

2013 ◽  
Vol 114 (11) ◽  
pp. 1527-1535 ◽  
Author(s):  
Desy Salvadego ◽  
Rossana Domenis ◽  
Stefano Lazzer ◽  
Simone Porcelli ◽  
Jörn Rittweger ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Resistance Training ◽  
Muscle Mass ◽  
Body Mass ◽  
Mitochondrial Respiration ◽  
Ex Vivo ◽  
Vastus Lateralis ◽  
Whole Body ◽  
Vastus Lateralis Muscle ◽  
Oxidative Function

Oxidative function during exercise was evaluated in 11 young athletes with marked skeletal muscle hypertrophy induced by long-term resistance training (RTA; body mass 102.6 ± 7.3 kg, mean ± SD) and 11 controls (CTRL; body mass 77.8 ± 6.0 kg). Pulmonary O2 uptake (V̇o2) 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). V̇o2peak during CE was higher in RTA vs. CTRL (4.05 ± 0.64 vs. 3.56 ± 0.30 l/min); 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), V̇o2 peak was lower (by 15–20%) in RTA vs. CTRL. Vastus lateralis fractional O2 extraction was lower in RTA vs. CTRL at all work rates, during both CE and KE. RTA had higher ADP-stimulated mitochondrial respiration (56.7 ± 23.7 pmol O2·s−1·mg−1 ww) vs. CTRL (35.7 ± 10.2 pmol O2·s−1·mg−1 ww) 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 mass.

scholarly journals Functional impairment of skeletal muscle oxidative metabolism during knee extension exercise after bed rest

2011 ◽  
Vol 111 (6) ◽  
pp. 1719-1726 ◽  
Author(s):  
Desy Salvadego ◽  
Stefano Lazzer ◽  
Mauro Marzorati ◽  
Simone Porcelli ◽  
Enrico Rejc ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Heart Rate ◽  
Blood Flow ◽  
Cardiac Output ◽  
Oxidative Metabolism ◽  
Near Infrared ◽  
Vastus Lateralis ◽  
Bed Rest ◽  
Knee Extension ◽  
Functional Evaluation

A functional evaluation of skeletal muscle oxidative metabolism during dynamic knee extension (KE) incremental exercises was carried out following a 35-day bed rest (BR) (Valdoltra 2008 BR campaign). Nine young male volunteers (age: 23.5 ± 2.2 yr; mean ± SD) were evaluated. Pulmonary gas exchange, heart rate and cardiac output (by impedance cardiography), skeletal muscle (vastus lateralis) fractional O2 extraction, and brain (frontal cortex) oxygenation (by near-infrared spectroscopy) were determined during incremental KE. Values at exhaustion were considered “peak”. Peak heart rate (147 ± 18 beats/min before vs. 146 ± 17 beats/min after BR) and peak cardiac output (17.8 ± 3.3 l/min before vs. 16.1 ± 1.8 l/min after BR) were unaffected by BR. As expected, brain oxygenation did not decrease during KE. Peak O2 uptake was lower after vs. before BR, both when expressed as liters per minute (0.99 ± 0.17 vs. 1.26 ± 0.27) and when normalized per unit of quadriceps muscle mass (46.5 ± 6.4 vs. 56.9 ± 11.0 ml·min−1·100 g−1). Skeletal muscle peak fractional O2 extraction, expressed as a percentage of the maximal values obtained during a transient limb ischemia, was lower after (46.3 ± 12.1%) vs. before BR (66.5 ± 11.2%). After elimination, by the adopted exercise protocol, of constraints related to cardiovascular O2 delivery, a decrease in peak O2 uptake and muscle peak capacity of fractional O2 extraction was found after 35 days of BR. These findings suggest a substantial impairment of oxidative function at the muscle level, “downstream” with respect to bulk blood flow to the exercising muscles, that is possibly at the level of blood flow distribution/O2 utilization inside the muscle, peripheral O2 diffusion, and intracellular oxidative metabolism.

scholarly journals MEF2 as upstream regulator of the transcriptome signature in human skeletal muscle during unloading

2018 ◽  
Vol 315 (4) ◽  
pp. R799-R809 ◽  
Author(s):  
Eric Rullman ◽  
Rodrigo Fernandez-Gonzalo ◽  
Igor B. Mekjavić ◽  
Thomas Gustafsson ◽  
Ola Eiken
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Vastus Lateralis ◽  
Bed Rest ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Gene Expression ◽  
Transcriptional Signature ◽  
Upstream Regulator ◽  
Transcriptome Signature

Our understanding of skeletal muscle structural and functional alterations during unloading has increased in recent decades, yet the molecular mechanisms underpinning these changes have only started to be unraveled. The purpose of the current investigation was to assess changes in skeletal muscle gene expression after 21 days of bed rest, with a particular focus on predicting upstream regulators of muscle disuse. Additionally, the association between differential microRNA expression and the transcriptome signature of bed rest were investigated. mRNAs from musculus vastus lateralis biopsies obtained from 12 men before and after the bed rest were analyzed using a microarray. There were 54 significantly upregulated probesets after bed rest, whereas 103 probesets were downregulated (false discovery rate 10%; fold-change cutoff ≥1.5). Among the upregulated genes, transcripts related to denervation-induced alterations in skeletal muscle were identified, e.g., acetylcholine receptor subunit delta and perinatal myosin. The most downregulated transcripts were functionally enriched for mitochondrial genes and genes involved in mitochondrial biogenesis, followed by a large number of contractile fiber components. Upstream regulator analysis identified a robust inhibition of the myocyte enhancer factor-2 (MEF2) family, in particular MEF2C, which was suggested to act upstream of several key downregulated genes, most notably peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α)/peroxisome proliferator-activated receptors (PPARs) and CRSP3. Only a few microRNAs were identified as playing a role in the overall transcriptome picture induced by sustained bed rest. Our results suggest that the MEF2 family is a key regulator underlying the transcriptional signature of bed rest and, hence, ultimately also skeletal muscle alterations induced by systemic unloading in humans.

Heterogeneity of human adaptations to bed rest and hypoxia: a retrospective analysis within the skeletal muscle oxidative function

2021 ◽  
Author(s):  
Desy Salvadego ◽  
Bruno Grassi ◽  
Michail E. Keramidas ◽  
Ola Eiken ◽  
Adam C. McDonnell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Respiration ◽  
Bed Rest ◽  
Knee Extension ◽  
Large Variability ◽  
The Individual ◽  
Oxidative Function ◽  
Knee Extension Exercise ◽  
Permeabilized Muscle

This retrospective study was designed to analyse the interindividual variability in the responses of different variables characterizing the skeletal muscle oxidative function to normoxic (N-BR) and hypoxic (H-BR) bed rests, and to a hypoxic ambulatory confinement (H-AMB) of 10 and 21 days. We also assessed whether and how the addition of hypoxia to bed rest might influence the heterogeneity of the responses. In vivo measurements of O2 uptake and muscle fractional O2 extraction were carried out during an incremental one-leg knee-extension exercise. Mitochondrial respiration was assessed in permeabilized muscle fibers. A total of 17 subjects were included in this analysis. This analysis revealed a similar variability among subjects in the alterations induced by N-BR and H-BR both in peak O2 uptake (SD: 4.1 and 3.3% after 10 days; 4.5 and 8.1% after 21 days, respectively) and peak muscle fractional O2 extraction (SD: 5.9 and 7.3% after 10 days; 6.5 and 7.3% after 21 days), independently from the duration of the exposure. The individual changes measured in these variables were significantly related (r=0.66, P=0.004 after N-BR; r=0.61, P=0.009 after H-BR). Mitochondrial respiration showed a large variability of response after both N-BR (SD: 25.0 and 15.7% after 10 and 21 days) and H-BR (SD: 13.0 and 19.8% after 10 and 21 days), no correlation was found between N-BR and H-BR changes. When added to bed rest, hypoxia altered the individual adaptations within the mitochondria but not those intrinsic to the muscle oxidative function in vivo, both after short and medium-term exposures.

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