scholarly journals Transcriptional pathways associated with skeletal muscle disuse atrophy in humans

2007 ◽  
Vol 31 (3) ◽  
pp. 510-520 ◽  
Author(s):  
Yi-Wen Chen ◽  
Chris M. Gregory ◽  
Mark T. Scarborough ◽  
Rongye Shi ◽  
Glenn A. Walter ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Healthy Volunteers ◽  
Muscle Function ◽  
Leptin Receptor ◽  
Medial Gastrocnemius ◽  
Disuse Atrophy ◽  
Rt Pcr ◽  
Cast Immobilization ◽  
Clinical Model ◽  
Genes Encoding

Disuse atrophy is a common clinical phenomenon that significantly impacts muscle function and activities of daily living. The purpose of this study was to implement genome-wide expression profiling to identify transcriptional pathways associated with muscle remodeling in a clinical model of disuse. Skeletal muscle biopsies were acquired from the medial gastrocnemius in patients with an ankle fracture and from healthy volunteers subjected to 4–11 days of cast immobilization. We identified 277 misregulated transcripts in immobilized muscles of patients, of which the majority were downregulated. The most broadly affected pathways were involved in energy metabolism, mitochondrial function, and cell cycle regulation. We also found decreased expression in genes encoding proteolytic proteins, calpain-3 and calpastatin, and members of the myostatin and IGF-I pathway. Only 26 genes showed increased expression in immobilized muscles, including apolipoprotein (APOD) and leptin receptor (LEPR). Upregulation of APOD (5.0-fold, P < 0.001) and LEPR (5.7-fold, P < 0.05) was confirmed by quantitative RT-PCR and immunohistochemistry. In addition, atrogin-1/MAFbx was found to be 2.4-fold upregulated ( P < 0.005) by quantitative RT-PCR. Interestingly, 96% of the transcripts differentially regulated in immobilized limbs also showed the same trend of change in the contralateral legs of patients but not the contralateral legs of healthy volunteers. Information obtained in this study complements findings in animal models of disuse and provides important feedback for future clinical studies targeting the restoration of muscle function following limb disuse in humans.

scholarly journals Phosphoproteomic identification of Xin as a novel requirement for skeletal muscle disuse atrophy

2019 ◽  
Author(s):  
Zhencheng Li ◽  
Pia Jensen ◽  
Johanna Abrigo ◽  
Carlos Henriquez-Olguin ◽  
Molly Gingrich ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Skeletal Muscle ◽  
Tibialis Anterior Muscle ◽  
Adaptor Protein ◽  
Disuse Atrophy ◽  
Cast Immobilization ◽  
Post Translational Modifications ◽  
Novel Proteins ◽  
Muscle Disuse

AbstractBackgroundImmobilization of skeletal muscle in a stretched position is associated with marked protection against disuse atrophy. Some intramyocellular changes in known proteins and post-translational modifications were previously linked to this phenomenon but there are likely many presently unknown proteins and post-translational modifications that contribute to this beneficial effect.MethodsTo identify novel proteins and phosphorylation events involved in stretch-induced reduction of disuse atrophy, we conducted a global unbiased screen of the changes occurring in skeletal muscle in control vs. 1 day and 1 week stretched cast-immobilized mouse tibialis anterior muscle, using quantitative tandem mass spectrometry on HILIC-fractionated muscle peptides with follow-up studies in transgenic mice and humans.ResultsOur mass spectrometry analyses detected 11714 phosphopeptides and 2081 proteins, of which 53 phosphopeptides and 5 proteins, 125 phosphopeptides and 43 proteins were deregulated after 1D and 7D of stretched immobilization, respectively. The sarcomere and muscle tendinous junction-associated putative multi-adaptor protein Xin was among the most highly upregulated proteins both in terms of phosphorylation and protein expression and was confirmed to increase with stretch but not disuse atrophy in mice and to increase and decrease with exercise and cast immobilization, respectively, in humans. Xin-/- mice were partially protected against disuse but not denervation atrophy in both stretched and flexed immobilized muscles compared to WT.ConclusionThis study identified Xin as a novel protein involved in disuse atrophy and also provides a resource to guide future hypothesis-driven investigations into uncovering critical factors in the protection against disuse atrophy.

scholarly journals Effects of microgravity on myogenic factor expressions during postnatal development of rat skeletal muscle

2002 ◽  
Vol 92 (5) ◽  
pp. 1936-1942 ◽  
Author(s):  
Manabu Inobe ◽  
Ikuko Inobe ◽  
Gregory R. Adams ◽  
Kenneth M. Baldwin ◽  
Shin'Ichi Takeda
Keyword(s):  
Skeletal Muscle ◽  
Postnatal Development ◽  
Tibialis Anterior ◽  
Skeletal Muscles ◽  
Medial Gastrocnemius ◽  
Rt Pcr ◽  
Specific Primers ◽  
Myogenic Factor ◽  
Semiquantitative Method

To clarify the role of gravity in the postnatal development of skeletal muscle, we exposed neonatal rats at 7 days of age to microgravity. After 16 days of spaceflight, tibialis anterior, plantaris, medial gastrocnemius, and soleus muscles were removed from the hindlimb musculature and examined for the expression of MyoD-family transcription factors such as MyoD, myogenin, and MRF4. For this purpose, we established a unique semiquantitative method, based on RT-PCR, using specific primers tagged with infrared fluorescence. The relative expression of MyoD in the tibialis anterior and plantaris muscles and that of myogenin in the plantaris and soleus muscles were significantly reduced ( P < 0.001) in the flight animals. In contrast, MRF4 expression was not changed in any muscle. These results suggest that MyoD and myogenin, but not MRF4, are sensitive to gravity-related stimuli in some skeletal muscles during postnatal development.

scholarly journals Skeletal muscle contractile properties in a novel murine model for limb girdle muscular dystrophy 2i

2017 ◽  
Vol 123 (6) ◽  
pp. 1698-1707 ◽  
Author(s):  
Jordan D. Rehwaldt ◽  
Buel D. Rodgers ◽  
David C. Lin
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Muscle Function ◽  
Contractile Properties ◽  
Limb Girdle Muscular Dystrophy ◽  
Medial Gastrocnemius ◽  
Active Force ◽  
Wild Type ◽  
Muscle Contractile Properties ◽  
Muscle Contractile

Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin-related protein and aberrant α-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. Therefore, we quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle of a novel model of LGMD2i. Normalized maximal twitch force, tetanic force, and power were significantly smaller in P448L mice, compared with sex-matched, wild-type mice. These differences were consistent with the replacement of contractile fibers by passive tissue. The shape of the active force-length relationships were similar in both groups, regardless of sex, consistent with an intact sarcomeric structure in P448L mice. Passive force-length curves normalized to maximal isometric force were steeper in P448L mice, and passive elements contribute disproportionately more to total contractile force in P448L mice. Sex differences were mostly noted in the force-velocity curves, as normalized values for maximal and optimal velocities were significantly slower in P448L males, compared with wild-type, but not in P448L females. This suggests that the dystrophic phenotype, which may include possible changes in cross-bridge kinetics and fiber-type proportions, progresses more quickly in P448L males. These results together indicate that active force and power generation are compromised in both sexes of P448L mice, while passive forces increase. More importantly, the results identified several functional markers of disease pathophysiology that could aid in developing and assessment of novel therapeutics for LGMD2i and possibly other dystroglycanopathies as well. NEW & NOTEWORTHY Comprehensive assessments of muscle contractile function have, until now, never been performed in an animal model for any dystroglycanopathy. This study suggests that skeletal muscle contractile properties are significantly compromised in a recently developed model for limb-girdle muscular dystrophy 2i, the P448L mouse. It further identifies novel pathological markers of muscle function that are suitable for developing therapeutics and for better understanding of disease pathogenesis.

scholarly journals Skeletal Muscle Disuse Atrophy and the Rehabilitative Role of Protein in Recovery from Musculoskeletal Injury

2020 ◽  
Vol 11 (4) ◽  
pp. 989-1001
Author(s):  
Emily E Howard ◽  
Stefan M Pasiakos ◽  
Maya A Fussell ◽  
Nancy R Rodriguez
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Dietary Protein ◽  
Muscle Function ◽  
Protein Intake ◽  
Musculoskeletal Injury ◽  
Physical Rehabilitation ◽  
Disuse Atrophy ◽  
Muscle Disuse

ABSTRACT Muscle atrophy and weakness occur as a consequence of disuse after musculoskeletal injury (MSI). The slow recovery and persistence of these deficits even after physical rehabilitation efforts indicate that interventions designed to attenuate muscle atrophy and protect muscle function are necessary to accelerate and optimize recovery from MSI. Evidence suggests that manipulating protein intake via dietary protein or free amino acid–based supplementation diminishes muscle atrophy and/or preserves muscle function in experimental models of disuse (i.e., immobilization and bed rest in healthy populations). However, this concept has rarely been considered in the context of disuse following MSI, which often occurs with some muscle activation during postinjury physical rehabilitation. Given that exercise sensitizes skeletal muscle to the anabolic effect of protein ingestion, early rehabilitation may act synergistically with dietary protein to protect muscle mass and function during postinjury disuse conditions. This narrative review explores mechanisms of skeletal muscle disuse atrophy and recent advances delineating the role of protein intake as a potential countermeasure. The possible synergistic effect of protein-based interventions and postinjury rehabilitation in attenuating muscle atrophy and weakness following MSI is also considered.

scholarly journals Atrophy Resistant vs. Atrophy Susceptible Skeletal Muscles: “aRaS” as a Novel Experimental Paradigm to Study the Mechanisms of Human Disuse Atrophy

2021 ◽  
Vol 12 ◽  
Author(s):  
Joseph J. Bass ◽  
Edward J. O. Hardy ◽  
Thomas B. Inns ◽  
Daniel J. Wilkinson ◽  
Mathew Piasecki ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Thickness ◽  
Muscle Volume ◽  
Medial Gastrocnemius ◽  
Skeletal Muscle Atrophy ◽  
Type I ◽  
Disuse Atrophy ◽  
Experimental Paradigm ◽  
Before And After ◽  
Mechanistic Basis

ObjectiveDisuse atrophy (DA) describes inactivity-induced skeletal muscle loss, through incompletely defined mechanisms. An intriguing observation is that individual muscles exhibit differing degrees of atrophy, despite exhibiting similar anatomical function/locations. We aimed to develop an innovative experimental paradigm to investigate Atrophy Resistant tibialis anterior (TA) and Atrophy Susceptible medial gastrocnemius (MG) muscles (aRaS) with a future view of uncovering central mechanisms.MethodSeven healthy young men (22 ± 1 year) underwent 15 days unilateral leg immobilisation (ULI). Participants had a single leg immobilised using a knee brace and air-boot to fix the leg (75° knee flexion) and ankle in place. Dual-energy X-ray absorptiometry (DXA), MRI and ultrasound scans of the lower leg were taken before and after the immobilisation period to determine changes in muscle mass. Techniques were developed for conchotome and microneedle TA/MG muscle biopsies following immobilisation (both limbs), and preliminary fibre typing analyses was conducted.ResultsTA/MG muscles displayed comparable fibre type distribution of predominantly type I fibres (TA 67 ± 7%, MG 63 ± 5%). Following 15 days immobilisation, MG muscle volume (–2.8 ± 1.4%, p &lt; 0.05) and muscle thickness decreased (−12.9 ± 1.6%, p &lt; 0.01), with a positive correlation between changes in muscle volume and thickness (R2 = 0.31, p = 0.038). Importantly, both TA muscle volume and thickness remained unchanged.ConclusionThe use of this unique “aRaS” paradigm provides an effective and convenient means by which to study the mechanistic basis of divergent DA susceptibility in humans, which may facilitate new mechanistic insights, and by extension, mitigation of skeletal muscle atrophy during human DA.

scholarly journals Skeletal muscle dysfunction in chronic renal failure: effects of exercise

2006 ◽  
Vol 290 (4) ◽  
pp. F753-F761 ◽  
Author(s):  
Gregory R. Adams ◽  
Nosratola D. Vaziri
Keyword(s):  
Skeletal Muscle ◽  
Renal Failure ◽  
Exercise Capacity ◽  
Muscle Function ◽  
Chronic Illnesses ◽  
Treatment Modalities ◽  
Muscle Dysfunction ◽  
Obstructive Pulmonary Disease ◽  
Skeletal Muscle Dysfunction

A number of chronic illnesses such as renal failure (CRF), obstructive pulmonary disease, and congestive heart failure result in a significant decrease in exercise tolerance. There is an increasing awareness that prescribed exercise, designed to restore some level of physical performance and quality of life, can be beneficial in these conditions. In CRF patients, muscle function can be affected by a number of direct and indirect mechanisms caused by renal disease as well as various treatment modalities. The aims of this review are twofold: first, to briefly discuss the mechanisms by which CRF negatively impacts skeletal muscle and, therefore, exercise capacity, and, second, to discuss the available data on the effects of programmed exercise on muscle function, exercise capacity, and various other parameters in CRF.

scholarly journals Gait disturbances and muscle dysfunction in fibroblast growth factor 2 knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Homer-Bouthiette ◽  
L. Xiao ◽  
Marja M. Hurley
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Strength ◽  
Fibroblast Growth Factor ◽  
Muscle Function ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Skeletal Muscle Function ◽  
Age Related ◽  
Gait Disturbances

AbstractFibroblast growth factor 2 (FGF2) is important in musculoskeletal homeostasis, therefore the impact of reduction or Fgf2 knockout on skeletal muscle function and phenotype was determined. Gait analysis as well as muscle strength testing in young and old WT and Fgf2KO demonstrated age-related gait disturbances and reduction in muscle strength that were exacerbated in the KO condition. Fgf2 mRNA and protein were significantly decreased in skeletal muscle of old WT compared with young WT. Muscle fiber cross-sectional area was significantly reduced with increased fibrosis and inflammatory infiltrates in old WT and Fgf2KO vs. young WT. Inflammatory cells were further significantly increased in old Fgf2KO compared with old WT. Lipid-related genes and intramuscular fat was increased in old WT and old Fgf2KO with a further increase in fibro-adipocytes in old Fgf2KO compared with old WT. Impaired FGF signaling including Increased β-Klotho, Fgf21 mRNA, FGF21 protein, phosphorylated FGF receptors 1 and 3, was observed in old WT and old Fgf2KO. MAPK/ ERK1/2 was significantly increased in young and old Fgf2KO. We conclude that Fgf2KO, age-related decreased FGF2 in WT mice, and increased FGF21 in the setting of impaired Fgf2 expression likely contribute to impaired skeletal muscle function and sarcopenia in mice.

scholarly journals Fourteen days of smoking cessation improves muscle fatigue resistance and reverses markers of systemic inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mohammad Z. Darabseh ◽  
Thomas M. Maden-Wilkinson ◽  
George Welbourne ◽  
Rob C. I. Wüst ◽  
Nessar Ahmed ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Smoking Cessation ◽  
Muscle Fatigue ◽  
Fatigue Resistance ◽  
Systemic Inflammation ◽  
Muscle Function ◽  
Low Grade ◽  
Skeletal Muscle Function ◽  
Tnf Α

AbstractCigarette smoking has a negative effect on respiratory and skeletal muscle function and is a risk factor for various chronic diseases. To assess the effects of 14 days of smoking cessation on respiratory and skeletal muscle function, markers of inflammation and oxidative stress in humans. Spirometry, skeletal muscle function, circulating carboxyhaemoglobin levels, advanced glycation end products (AGEs), markers of oxidative stress and serum cytokines were measured in 38 non-smokers, and in 48 cigarette smokers at baseline and after 14 days of smoking cessation. Peak expiratory flow (p = 0.004) and forced expiratory volume in 1 s/forced vital capacity (p = 0.037) were lower in smokers compared to non-smokers but did not change significantly after smoking cessation. Smoking cessation increased skeletal muscle fatigue resistance (p < 0.001). Haemoglobin content, haematocrit, carboxyhaemoglobin, total AGEs, malondialdehyde, TNF-α, IL-2, IL-4, IL-6 and IL-10 (p < 0.05) levels were higher, and total antioxidant status (TAS), IL-12p70 and eosinophil numbers were lower (p < 0.05) in smokers. IL-4, IL-6, IL-10 and IL-12p70 had returned towards levels seen in non-smokers after 14 days smoking cessation (p < 0.05), and IL-2 and TNF-α showed a similar pattern but had not yet fully returned to levels seen in non-smokers. Haemoglobin, haematocrit, eosinophil count, AGEs, MDA and TAS did not significantly change with smoking cessation. Two weeks of smoking cessation was accompanied with an improved muscle fatigue resistance and a reduction in low-grade systemic inflammation in smokers.

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