Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength.
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ABSTRACT:
SUBMITTER: Summermatter S
PROVIDER: S-EPMC5311239 | biostudies-other | 2017 Mar
REPOSITORIES: biostudies-other
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Project description:BackgroundGrowth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily. The GDF11 propeptide, which is derived from the GDF11 precursor protein, blocks the activity of GDF11 and its homolog, myostatin, which are both potent inhibitors of muscle growth. Thus, treatment with GDF11 propeptide may be a potential therapeutic strategy for diseases associated with muscle atrophy like sarcopenia and the muscular dystrophies. Here, we evaluate the impact of GDF11 propeptide-Fc (GDF11PRO-Fc) gene delivery on skeletal muscle in normal and dystrophic adult mice.MethodsA pull-down assay was used to obtain physical confirmation of a protein-protein interaction between GDF11PRO-Fc and GDF11 or myostatin. Next, differentiated C2C12 myotubes were treated with AAV6-GDF11PRO-Fc and challenged with GDF11 or myostatin to determine if GDF11PRO-Fc could block GDF11/myostatin-induced myotube atrophy. Localized expression of GDF11PRO-Fc was evaluated via a unilateral intramuscular injection of AAV9-GDF11PRO-Fc into the hindlimb of C57BL/6J mice. In mdx mice, intravenous injection of AAV9-GDF11PRO-Fc was used to achieve systemic expression. The impact of GDF11PRO-Fc on muscle mass, function, and pathological features were assessed.ResultsGDF11PRO-Fc was observed to bind both GDF11 and myostatin. In C2C12 myotubes, expression of GDF11PRO-Fc was able to mitigate GDF11/myostatin-induced atrophy. Following intramuscular injection in C57BL/6J mice, increased grip strength and localized muscle hypertrophy were observed in the injected hindlimb after 10 weeks. In mdx mice, systemic expression of GDF11PRO-Fc resulted in skeletal muscle hypertrophy without a significant change in cardiac mass after 12 weeks. In addition, grip strength and rotarod latency time were improved. Intramuscular fibrosis was also reduced in treated mdx mice; however, there was no change seen in central nucleation, membrane permeability to serum IgG or serum creatine kinase levels.ConclusionsGDF11PRO-Fc induces skeletal muscle hypertrophy and improvements in muscle strength via inhibition of GDF11/myostatin signaling. However, GDF11PRO-Fc does not significantly improve the dystrophic pathology in mdx mice.
| S-EPMC6537384 | biostudies-literature
Project description:Androgens have a robust effect on skeletal muscles to increase muscle mass and strength. The molecular mechanism of androgen/androgen receptor (AR) action on muscle strength is still not well known, especially for the regulation of sarcomeric genes. In this study, we generated androgen-induced hypertrophic model mice, myofiber-specific androgen receptor knockout (cARKO) mice supplemented with dihydrotestosterone (DHT). DHT treatment increased grip strength in control mice but not in cARKO mice. Transcriptome analysis by RNA-seq, using skeletal muscles obtained from control and cARKO mice treated with or without DHT, identified a fast-type muscle-specific novel splicing variant of Myosin light-chain kinase 4 (Mylk4) as a target of AR in skeletal muscles. Mylk4 knockout mice exhibited decreased maximum isometric torque of plantar flexion and passive stiffness of myofibers due to reduced phosphorylation of Myomesin 1 protein. This study suggests that androgen-induced skeletal muscle strength is mediated with Mylk4 and Myomesin 1 axis.
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Project description:Maslinic acid (MA) is a pentacyclic triterpene abundant in olive peels. MA reportedly increases skeletal muscle mass and strength in older adults; however, the underlying mechanism is unknown. This study aimed to investigate the effects of MA on denervated muscle atrophy and strength and to explore the underlying molecular mechanism. Mice were fed either a control diet or a 0.27% MA diet. One week after intervention, the sciatic nerves of both legs were cut to induce muscle atrophy. Mice were examined 14 days after denervation. MA prevented the denervation-induced reduction in gastrocnemius muscle mass and skeletal muscle strength. Microarray gene expression profiling in gastrocnemius muscle demonstrated several potential mechanisms for muscle maintenance. Gene set enrichment analysis (GSEA) revealed different enriched biological processes, such as myogenesis, PI3/AKT/mTOR signaling, TNFα signaling via NF-κB, and TGF-β signaling in MA-treated mice. In addition, qPCR data showed that MA induced Igf1 expression and suppressed the expressions of Atrogin-1, Murf1 and Tgfb. Altogether, our results suggest the potential of MA as a new therapeutic and preventive dietary ingredient for muscular atrophy and strength.
| S-EPMC8468537 | biostudies-literature
Project description:Dysphagia is frequently observed in patients with chronic obstructive pulmonary disease (COPD). Decreased tongue strength is one of the causes of dysphagia, and it is often observed in patients with sarcopenia. Sarcopenia is also frequently observed in COPD patients. We hypothesized that tongue strength is lower in COPD patients compared to normal subjects. This was a single-center, observational, cross-sectional study. Maximum tongue pressure (MTP) was measured in 27 patients with COPD and 24 age-matched control subjects. We also evaluated handgrip strength, gait speed, and appendicular skeletal muscle mass to define subjects as having sarcopenia. We used bioelectrical impedance analysis to assess body composition. The eating assessment test-10 was used to diagnose dysphagia. MTP was significantly lower in COPD patients than in control subjects (33.8 ± 8.4 vs 38.0 ± 5.3; p = 0.032). All measures of muscle and fat free body mass, handgrip strength, and gait speed were also significantly lower in COPD patients compared to control subjects (p < 0.01). The prevalence of sarcopenia in COPD patients was higher than that in control subjects (6/27 versus 0/24; p = 0.007), but the prevalence of dysphagia was not different between groups (COPD: 5/27, versus control: 1/24; p = 0.112). MTP was moderately correlated with skeletal muscle mass index (r = 0.56, p = 0.003) and handgrip strength (r = 0.43, p = 0.027) in COPD patients. Tongue strength was lower in COPD patients compared to normal subjects, and decreased tongue strength may be correlated with sarcopenia in COPD patients.
| S-EPMC8149139 | biostudies-literature
Project description:The microgravity conditions of prolonged spaceflight are known to result in skeletal muscle atrophy that leads to diminished functional performance. To assess if inhibition of the growth factor myostatin has potential to reverse these effects, mice were treated with a myostatin antibody while housed on the International Space Station. Grip strength of ground control mice increased 3.1% compared to baseline values over the 6 weeks of the study, whereas grip strength measured for the first time in space showed flight animals to be -7.8% decreased in strength compared to baseline values. Control mice in space exhibited, compared to ground-based controls, a smaller increase in DEXA-measured muscle mass (+3.9% vs +5.6% respectively) although the difference was not significant. All individual flight limb muscles analyzed (except for the EDL) weighed significantly less than their ground counterparts at the study end (range -4.4% to -28.4%). Treatment with myostatin antibody YN41 was able to prevent many of these space-induced muscle changes. YN41 was able to block the reduction in muscle grip strength caused by spaceflight and was able to significantly increase the weight of all muscles of flight mice (apart from the EDL). Muscles of YN41-treated flight mice weighed as much as muscles from Ground IgG mice, with the exception of the soleus, demonstrating the ability to prevent spaceflight-induced atrophy. Muscle gene expression analysis demonstrated significant effects of microgravity and myostatin inhibition on many genes. Gamt and Actc1 gene expression was modulated by microgravity and YN41 in opposing directions. Myostatin inhibition did not overcome the significant reduction of microgravity on femoral BMD nor did it increase femoral or vertebral BMD in ground control mice. In summary, myostatin inhibition may be an effective countermeasure to detrimental consequences of skeletal muscle under microgravity conditions.
| S-EPMC7173869 | biostudies-literature
Project description:BackgroundMeasures of skeletal muscle function decline at a faster rate with ageing than do indices of skeletal muscle mass. These observations have been attributed to age-related changes in muscle quality, another functional determinant separate from skeletal muscle mass. This study tested the hypothesis that improved predictions of skeletal muscle strength can be accomplished by combining clinically available measures of skeletal muscle mass and quality.MethodsThe participants included 146 healthy adult (age ≥ 18 years, range 18-77 years; X ± SD 47 ± 17 years and body mass index 16.5-51.8 kg/m2 ; 27.7 ± 6.2 kg/m2 ) men (n = 60) and women (n = 86) in whom skeletal muscle mass was estimated as appendicular lean soft tissue (LST) measured by dual-energy X-ray absorptiometry and skeletal muscle quality as bioimpedance analysis-derived phase angle and B-mode-evaluated echogenicity of mid-thigh skeletal muscle. Strength of the right leg and both arms was quantified as knee isokinetic extension and handgrip strength using dynamometers. The statistical significance of adding phase angle or echogenicity to strength prediction multiple regression models that included extremity-specific LST and other covariates (e.g. age and sex) was evaluated to test the study hypothesis.ResultsRight leg LST mass alone was significantly (P < 0.0001) correlated with isokinetic right leg strength (R2 = 0.57). The addition of segmental phase angle measured in the right leg at 50 kHz increased the R2 of this model to 0.66 (P < 0.0001); other phase angle frequencies (5 and 250 kHz) did not contribute significantly to these models. Results were similar for both right and left arm handgrip strength prediction models. Adding age and sex as model covariates increased the R2 values of these models further (e.g. right leg strength model R2 increased to 0.71), but phase angle continued to remain a significant (all P < 0.01) predictor of extremity strength. Similarly, when predicting isokinetic right leg strength, mid-thigh skeletal muscle echogenicity added significantly (P < 0.0001) to right leg LST, increasing R2 from 0.57 to 0.64; age was a significant (P < 0.0001) covariate in this model, increasing R2 further to 0.68.ConclusionsThe hypothesis of the current study was confirmed, strongly supporting and extending earlier reports by quantifying the combined independent effects of skeletal muscle mass and quality on lower-body and upper-body measures of strength. These observations provide a clinically available method for future research aimed at optimizing sarcopenia and frailty risk prediction models.
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Project description:NF-kappaB is a major pleiotropic transcription factor modulating immune, inflammatory, cell survival, and proliferative responses, yet the relevance of NF-kappaB signaling in muscle physiology and disease is less well documented. Here we show that muscle-restricted NF-kappaB inhibition in mice, through targeted deletion of the activating kinase inhibitor of NF-kappaB kinase 2 (IKK2), shifted muscle fiber distribution and improved muscle force. In response to denervation, IKK2 depletion protected against atrophy, maintaining fiber type, size, and strength, increasing protein synthesis, and decreasing protein degradation. IKK2-depleted mice with a muscle-specific transgene expressing a local Igf-1 isoform (mIgf-1) showed enhanced protection against muscle atrophy. In response to muscle damage, IKK2 depletion facilitated skeletal muscle regeneration through enhanced satellite cell activation and reduced fibrosis. Our results establish IKK2/NF-kappaB signaling as an important modulator of muscle homeostasis and suggest a combined role for IKK inhibitors and growth factors in the therapy of muscle diseases.
| S-EPMC1626136 | biostudies-literature
Project description:Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid's effects on muscle were accompanied by reductions in adiposity, fasting blood glucose, and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases.
| S-EPMC3120768 | biostudies-literature
Project description:BackgroundIdentifying low skeletal muscle strength (SMS), skeletal muscle mass (SMM) and skeletal muscle quality (SMQ) is pivotal for diagnosing sarcopenia cases. Age-related declines in SMS, SMM, and SMQ are dissimilar between the upper (UL) and lower limbs (LL). Despite this, both UL and LL measures have been used to assess SMS, SMM and SMQ in older adults. However, it is not clear whether there is agreement between UL and LL measures to identify older adults with low SMS, SMM and SMQ.ObjectiveTo investigate the agreement between UL and LL measures to identify older adults with low SMS, SMM and SMQ.MethodsParticipants (n = 385; 66.1 ± 5.1 years; 75,4% females) performed the handgrip strength test (HGS) and the 30-s chair stand test (CST) to assess UL- and LL-SMS, respectively. The SMM was assessed by dual-energy X-ray absorptiometry (DXA). The UL-SMQ was determined as: handgrip strength (kgf) ÷ arm SMM (kg). LL-SMQ was determined as: 30-s CST performance (repetitions) ÷ leg SMM (kg). Results below the 25th percentile stratified by sex and age group (60-69 and 70-80 years) were used to determine low SMS, SMM and SMQ. Cohen's kappa coefficient (κ) was used for the agreement analyses.ResultsThere was a slight and non-significant agreement between UL and LL measures to identify older adults with low SMS (κ = 0.046; 95% CI 0.093-0.185; p = 0.352). There was a moderate agreement to identify low SMM (κ = 0.473; 95% CI 0.371-0.574; p = 0.001) and a fair agreement to identify low SMQ (κ = 0.206; 95% CI 0.082 to 0.330; p = 0.005).ConclusionThe agreement between UL and LL measures to identify older adults with low SMS, SMM and SMQ is limited, which might generate different clinical interpretations for diagnosing sarcopenia cases.
| S-EPMC8782376 | biostudies-literature
Project description:BACKGROUND:Inflammation and skeletal muscle wasting often coexist in elderly populations, but few studies have examined their relationship in elderly heart failure (HF) patients. This study examined the relationship between inflammation and increased skeletal muscle proteolysis, reduced skeletal mass and strength, and their prognostic implications in elderly HF patients (> 65?years) using a random forest approach. METHODS:We prospectively enrolled consecutive elderly HF patients (n?=?78) and age- and sex-matched control subjects (n?=?83). We measured the interleukin (IL)-6, C-reactive protein (CRP), and B-type natriuretic peptide (BNP) levels, lower limb muscle mass and strength, and 6-min walk distance. The amount of muscle proteolysis was determined by urinary 3-methylhystidine, normalized by creatinine (3-MH/Cr). The composite endpoint was defined as all-cause death or hospitalizations due to worsening HF. RESULTS:Compared to controls, elderly HF patients had a significantly higher IL-6, CRP, BNP, and 3-MH/Cr, and exhibited a reduced lower limb muscle mass and strength. A correlation analysis demonstrated significant positive correlations between the inflammatory cytokine levels and 3-MH/Cr and BNP, and negative correlations with the lower limb muscle mass and strength, and 6-min walk distance. During a median follow-up of 2.4-years, 24 patients reached the endpoint. A random forest model revealed that inflammatory cytokines, skeletal muscle wasting, and the BNP had greater effects on the risk prediction. The algorithm achieved an area under the receiver operating characteristic curve of 0.887 (95% CI, 0.772-1.000). CONCLUSION:This study provided evidence of the association between inflammation and increased skeletal muscle proteolysis, reduced skeletal mass and strength, and their prognostic roles in elderly HF patients.
| S-EPMC7229573 | biostudies-literature