Short-term bed rest increases TLR4 and IL-6 expression in skeletal muscle of 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.

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Age-dependent skeletal muscle transcriptome response to bed rest-induced atrophy

Journal of Applied Physiology ◽

10.1152/japplphysiol.00811.2018 ◽

2019 ◽

Vol 126 (4) ◽

pp. 894-902 ◽

Cited By ~ 10

Author(s):

Ziad S. Mahmassani ◽

Paul T. Reidy ◽

Alec I. McKenzie ◽

Chris Stubben ◽

Michael T. Howard ◽

...

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Cell Adhesion ◽

Lean Mass ◽

Muscle Wasting ◽

Stellate Cell ◽

Bed Rest ◽

Muscle Loss ◽

Short Term ◽

Adult Skeletal Muscle

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.

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

JAMA ◽

10.1001/jama.297.16.1772-b ◽

2007 ◽

Vol 297 (16) ◽

pp. 1769 ◽

Cited By ~ 404

Author(s):

Patrick Kortebein ◽

Arny Ferrando ◽

Juan Lombeida ◽

Robert Wolfe ◽

William J. Evans

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Bed Rest ◽

Healthy Older Adults

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Short‐term bed rest increases inflammation as evidenced by elevated TLR4, NFκB1 and IL6 expression in skeletal muscle of older adults

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.715.2 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Micah J Drummond ◽

Kyle L Timmerman ◽

Melissa M Markofski ◽

Dillon K Walker ◽

Jared M Dickinson ◽

...

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Bed Rest ◽

Short Term

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Short-term Effects of Whole-Body Vibration on Functional Mobility and Flexibility in Healthy, Older Adults

Journal of Geriatric Physical Therapy ◽

10.1519/jpt.0b013e318295dacd ◽

2014 ◽

Vol 37 (2) ◽

pp. 58-64 ◽

Cited By ~ 8

Author(s):

Taishi Tsuji ◽

Naruki Kitano ◽

Kenji Tsunoda ◽

Erika Himori ◽

Tomohiro Okura ◽

...

Keyword(s):

Older Adults ◽

Whole Body Vibration ◽

Functional Mobility ◽

Whole Body ◽

Short Term ◽

Healthy Older Adults ◽

Body Vibration ◽

Short Term Effects

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Specific impairments in visuospatial working and short-term memory following low-dose scopolamine challenge in healthy older adults

Neuropsychologia ◽

10.1016/j.neuropsychologia.2008.04.010 ◽

2008 ◽

Vol 46 (10) ◽

pp. 2476-2484 ◽

Cited By ~ 32

Author(s):

Elizabeth Thomas ◽

Peter J. Snyder ◽

Robert H. Pietrzak ◽

Colleen E. Jackson ◽

Martin Bednar ◽

...

Keyword(s):

Older Adults ◽

Low Dose ◽

Short Term Memory ◽

Short Term ◽

Term Memory ◽

Healthy Older Adults

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.00810.2020 ◽

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.

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The ZBED6–IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1719278115 ◽

2018 ◽

Vol 115 (9) ◽

pp. E2048-E2057 ◽

Cited By ~ 15

Author(s):

Shady Younis ◽

Milena Schönke ◽

Julie Massart ◽

Rikke Hjortebjerg ◽

Elisabeth Sundström ◽

...

Keyword(s):

Skeletal Muscle ◽

Binding Site ◽

Lean Mass ◽

Transcriptome Analysis ◽

Subcutaneous Fat ◽

Biological Significance ◽

Internal Organs ◽

Adult Skeletal Muscle ◽

Knock Out ◽

Extracellular Region

A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6–IGF2 interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out (Zbed6−/−) and Igf2 knock-in mice that carry the pig IGF2 mutation. These transgenic mice exhibit markedly higher serum IGF2 concentrations, higher growth rate, increased lean mass, and larger heart, kidney, and liver; no significant changes were observed for white adipose tissues. The changes in body and lean mass were most pronounced in female mice. The phenotypic changes were concomitant with a remarkable up-regulation of Igf2 expression in adult tissues. Transcriptome analysis of skeletal muscle identified differential expression of genes belonging to the extracellular region category. Expression analysis using fetal muscles indicated a minor role of ZBED6 in regulating Igf2 expression prenatally. Furthermore, transcriptome analysis of the adult skeletal muscle revealed that this elevated expression of Igf2 was derived from the P1 and P2 promoters. The results revealed very similar phenotypic effects in the Zbed6 knock-out mouse and in the Igf2 knock-in mouse, showing that the effect of ZBED6 on growth of muscle and internal organs is mediated through the binding site in the Igf2 gene. The results explain why this ZBED6 binding site is extremely well conserved among placental mammals.

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Reduced physical activity in young and older adults: metabolic and musculoskeletal implications

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018819888824 ◽

2019 ◽

Vol 10 ◽

pp. 204201881988882 ◽

Cited By ~ 16

Author(s):

Kelly A. Bowden Davies ◽

Samuel Pickles ◽

Victoria S. Sprung ◽

Graham J. Kemp ◽

Uazman Alam ◽

...

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Older Adults ◽

Skeletal Muscle ◽

High Risk ◽

Physical Inactivity ◽

Hepatic Insulin Resistance ◽

Short Term ◽

Peripheral Insulin Resistance ◽

Triglyceride Accumulation

Background: Although the health benefits of regular physical activity and exercise are well established and have been incorporated into national public health recommendations, there is a relative lack of understanding pertaining to the harmful effects of physical inactivity. Experimental paradigms including complete immobilization and bed rest are not physiologically representative of sedentary living. A useful ‘real-world’ approach to contextualize the physiology of societal downward shifts in physical activity patterns is that of short-term daily step reduction. Results: Step-reduction studies have largely focused on musculoskeletal and metabolic health parameters, providing relevant disease models for metabolic syndrome, type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), sarcopenia and osteopenia/osteoporosis. In untrained individuals, even a short-term reduction in physical activity has a significant impact on skeletal muscle protein and carbohydrate metabolism, causing anabolic resistance and peripheral insulin resistance, respectively. From a metabolic perspective, short-term inactivity-induced peripheral insulin resistance in skeletal muscle and adipose tissue, with consequent liver triglyceride accumulation, leads to hepatic insulin resistance and a characteristic dyslipidaemia. Concomitantly, various inactivity-related factors contribute to a decline in function; a reduction in cardiorespiratory fitness, muscle mass and muscle strength. Conclusions: Physical inactivity maybe particularly deleterious in certain patient populations, such as those at high risk of T2D or in the elderly, considering concomitant sarcopenia or osteoporosis. The effects of short-term physical inactivity (with step reduction) are reversible on resumption of habitual physical activity in younger people, but less so in older adults. Nutritional interventions and resistance training offer potential strategies to prevent these deleterious metabolic and musculoskeletal effects. Impact: Individuals at high risk of/with cardiometabolic disease and older adults may be more prone to these acute periods of inactivity due to acute illness or hospitalization. Understanding the risks is paramount to implementing countermeasures.

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Leucine Supplementation Partially Protects Leg Lean Mass in Older Adults During Seven Days of Bed Rest (OR18-02-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz028.or18-02-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Emily Arentson-Lantz ◽

Fego Galvan ◽

Rachel Deer ◽

Adam Wacher ◽

Doug Paddon-Jones

Keyword(s):

Older Adults ◽

Clinical Research ◽

Muscle Fiber ◽

Lean Mass ◽

Fiber Type ◽

Bed Rest ◽

Research Center ◽

Leucine Supplementation ◽

Clinical Research Center ◽

Increased Risk

Abstract Objectives Older adults are at increased risk of being hospitalized or bedridden and experiencing a host of negative health outcomes including loss of lean body mass. We hypothesized that supplementing daily meals with a small quantity (3–4 g/meal) of leucine will partially preserve lean leg mass and function during bed rest. Methods Men and women (67.8 ± 1.1 y) were randomized to receive isoenergentic meals supplemented with leucine (LEU, 0.06 g/kg/meal; n = 10) or an alanine control, (CON, 0.06 g/kg/meal; n = 10). Subjects were admitted to the Clinical Research Center for 7 days of bed rest followed by 7 days of rehabilitation. Muscle fiber type and cross-sectional area (CSA) as well as single fiber characteristics were assessed from biopsies of the vastus lateralis obtained prior to (Pre-BR) and after bed rest (Post-BR) and after rehabilitation (Post-RE). Body composition measured using iDEXA was also determined at the same time points. Results Leucine-supplementation partially protected leg lean mass during bed rest (−1035 vs. −423 ± 143 g; P = 0.008). Leg lean mass did not differ between the groups Post-RE (P = 0.16). There was no significant effect of time (P = 0.16) or treatment (P = 0.92) on muscle fiber CSA; however, CON subjects, but not LEU subjects, exhibited an increased number of smaller fibers (<2000 um) and fewer larger fibers (>6000 um) Post-BR. Additionally, CON subjects tended to have a greater decrement in fiber width (P = 0.085) that did not return to baseline following rehabilitation. Conclusions Supplementing older adults with moderate amounts of leucine has the potential to partially negate some of the deleterious effects on muscle health during short bouts of inactivity. Funding Sources National Institutes of Health, The Claude D. Pepper Older Americans Independence Center, Sealy Center on Aging and Institute for Translational Sciences-Clinical Research Center.

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