Modified forelimb grip strength test detects aging-associated physiological decline in skeletal muscle function in male mice

This study investigated the effects of resveratrol feeding and exercise training on the skeletal muscle function and transcriptome of aged rats. Male SD rats (25 months old) were divided into the control group (Old), the daily exercise training group (Trained), and the resveratrol feeding group (Resveratrol). After 6 weeks of intervention, the body mass, grip strength, and gastrocnemius muscle mass were determined, and the muscle samples were analyzed by transcriptome sequencing. The differentially expressed genes were analyzed followed by GO enrichment analysis and KEGG analysis. The Old group showed positive increases in body mass, while both the Trained and Resveratrol groups showed negative growth. No significant differences in the gastrocnemius muscle index and absolute grip strength were found among the three groups. However, the relative grip strength was higher in the Trained group than in the Old group. Only 21 differentially expressed genes were identified in the Trained group vs. the Old group, and 12 differentially expressed genes were identified in the Resveratrol group vs. the Old group. The most enriched GO terms in the Trained group vs. the Old group were mainly associated with RNA metabolic processes and transmembrane transporters, and the significantly upregulated KEGG pathways included mucin-type O-glycan biosynthesis, drug metabolism, and pyrimidine metabolism. The most enriched GO terms in the Resveratrol group vs. the Old group were primarily associated with neurotransmitter transport and synaptic vesicle, and the upregulated KEGG pathways included synaptic vesicle cycle, nicotine addiction, retinol metabolism, insulin secretion, retrograde endocannabinoid signaling, and glutamatergic synapse. Neither exercise training nor resveratrol feeding has a notable effect on skeletal muscle function and related gene expression in aged rats. However, both exercise training and resveratrol feeding have strong effects on weight loss, which is beneficial for reducing the exercise loads of the elderly.

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Assessing the Use of the sGC Stimulator BAY-747, as a Potential Treatment for Duchenne Muscular Dystrophy

International Journal of Molecular Sciences ◽

10.3390/ijms22158016 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8016

Author(s):

Shalini Murali Krishnan ◽

Johannes Nordlohne ◽

Lisa Dietz ◽

Alexandros Vakalopoulos ◽

Petra Haning ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Grip Strength ◽

Muscle Function ◽

Phase Iii ◽

Potential Treatment ◽

Skeletal Muscle Function ◽

Therapeutic Benefits ◽

Sgc Stimulators

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.

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Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00607.2012 ◽

2013 ◽

Vol 114 (9) ◽

pp. 1340-1350 ◽

Cited By ~ 12

Author(s):

Kechun Tang ◽

George Murano ◽

Harrieth Wagner ◽

Leonardo Nogueira ◽

Peter D. Wagner ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Capacity ◽

Muscle Function ◽

Citrate Synthase ◽

Left Ventricular ◽

Lv Function ◽

Male Mice ◽

Skeletal Muscle Function ◽

Exercise Limitation ◽

Maximal Pressure

Pulmonary TNFα has been linked to reduced exercise capacity in a subset of patients with moderate to severe chronic obstructive pulmonary disease (COPD). We hypothesized that prolonged, high expression of pulmonary TNFα impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNFα construct, TNFα was overexpressed throughout life in mouse lungs (SP-C/TNFα+). TNFα levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNFα+ mice, TNFα increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNFα+ mice. While increases in lung volume and airspace size induced by TNFα were comparable in both sexes, pulmonary hypertension along with lower body and muscle mass were evident only in male mice. Left ventricular (LV) function (cardiac output, stroke volume, LV maximal pressure, and LV maximal pressure dP/d t) was not altered by TNFα overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNFα+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1α mRNA and increase in atrogin-1 and MuRF1 expression also only in male mice. In situ gastrocnemius fatigue resistance, reflecting both oxygen availability and contractility, was decreased similarly in female and male SP-C/TNFα+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNFα are susceptible to exercise limitation, possibly due to muscle wasting and loss of the oxidative muscle phenotype, with protection in females possibly due to estrogen.

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Exercise Preconditioning Preserves Skeletal Muscle Function and Stunts Tumor Growth in Male Mice

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.05484 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

T. J. Brantley ◽

Louisa Tichy ◽

George Blackburn ◽

Traci Parry

Keyword(s):

Skeletal Muscle ◽

Tumor Growth ◽

Muscle Function ◽

Male Mice ◽

Skeletal Muscle Function ◽

Exercise Preconditioning

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Faculty Opinions recommendation of TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1556023.1047131 ◽

2010 ◽

Author(s):

Annemie Schols ◽

Harry Gosker

Keyword(s):

Skeletal Muscle ◽

Cigarette Smoke ◽

Muscle Function ◽

Smoke Exposure ◽

Tnf Alpha ◽

Cigarette Smoke Exposure ◽

Skeletal Muscle Function ◽

Mediated Reduction

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

Scientific Reports ◽

10.1038/s41598-021-90565-0 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-021-91510-x ◽

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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