Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy

Lee, Yun Sil; Lehar, Adam; Sebald, Suzanne M.; Liu, Min; Swaggart, Kayleigh A.; Talbot, C. Conover; Pytel, Peter; Barton, Elisabeth R.; McNally, Elizabeth M.; Lee, Se Jin

doi:10.1093/hmg/ddv288

Cited by 37 publications

(45 citation statements)

References 30 publications

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“…When challenged with genetic gain of follistatin expression, a prohypertrophic manipulation, Dysf-null muscles showed exacerbation of muscle degeneration. 58 More refined studies, especially with treatment duration >4 weeks, are required to shed light on the interplays between intermittent steroid dosing and muscle mass remodeling pathways. However, these data support further investigation into mechanisms and biomarkers of these divergent steroid effects so that these preclinical findings can be translated into humans with muscle disease.…”

Section: Daily Prednisone Promoted Marked Adipogenesis In Dysferlin-dmentioning

confidence: 99%

Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy

Quattrocelli

Salamone

Page

et al. 2017

The American Journal of Pathology

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The muscular dystrophies are genetically diverse. Shared pathological features among muscular dystrophies include breakdown, or loss of muscle, and accompanying fibrotic replacement. Novel strategies are needed to enhance muscle repair and function and to slow this pathological remodeling. Glucocorticoid steroids, like prednisone, are known to delay loss of ambulation in patients with Duchenne muscular dystrophy but are accompanied by prominent adverse effects. However, less is known about the effects of steroid administration in other types of muscular dystrophies, including limb-girdle muscular dystrophies (LGMDs). LGMD 2B is caused by loss of dysferlin, a membrane repair protein, and LGMD 2C is caused by loss of the dystrophin-associated protein, γ-sarcoglycan. Herein, we assessed the efficacy of steroid dosing on sarcolemmal repair, muscle function, histopathology, and the regenerative capacity of primary muscle cells. We found that in murine models of LGMD 2B and 2C, daily prednisone dosing reduced muscle damage and fibroinflammatory infiltration. However, daily prednisone dosing also correlated with increased muscle adipogenesis and atrophic remodeling. Conversely, intermittent dosing of prednisone, provided once weekly, enhanced muscle repair and did not induce atrophy or adipogenesis, and was associated with improved muscle function. These data indicate that dosing frequency of glucocorticoid steroids affects muscle remodeling in non-Duchenne muscular dystrophies, suggesting a positive outcome associated with intermittent steroid dosing in LGMD 2B and 2C muscle.

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Section: Daily Prednisone Promoted Marked Adipogenesis In Dysferlin-dmentioning

confidence: 99%

Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy

Quattrocelli

Salamone

Page

et al. 2017

The American Journal of Pathology

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“…Another important finding in the present study is the increased follistatin mRNA levels after AET. Previous studies have demonstrated a significant relationship between follistatin and muscle growth and/or hypertrophy . Actually, Sun et al .…”

Section: Discussionmentioning

confidence: 99%

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

Antunes‐Correa

Trevizan

Bacurau

et al. 2019

J cachexia sarcopenia muscle

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Background The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA‐1 expression and downstream‐associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients. Methods Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II–III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months. Results Thirty‐three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA‐1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = −15 ± 0.03%), and tended to increase the p‐AKTser473/AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = −40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross‐sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA‐1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51). Conclusions AET upregulates microRNA‐1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K‐AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA‐1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross‐sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA‐1 and in the downstream‐associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. http://ClinicalTrials.gov (Identifier: NCT01747395)

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“…At 5 days, myotubes were exposed to different Folfiri (50 μg/ml 5-FU, 10 μg/ml Leucovorin, 20 μg/ml CPT-11; Sigma Aldrich, St. Louis, MO), in combination with either PD98059 (20 μM; Selleckchem, Houston, TX) or ACVR2B/Fc (10 μg/ml) or for up to 48h. ACVR2B/Fc protein expression from the stable Chinese hamster ovary (CHO) cells was induced with 100 nM Cadmium in serum-free CHO media, and ACVR2B/Fc protein was purified from the conditioned medium using protein A Sepharose, as shown in [64]. CHO-ACVR2B/Fc cells were a kind gift of Dr. See-Jin Lee (Johns Hopkins University, Baltimore, MD).…”

Section: Methodsmentioning

confidence: 99%

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

et al. 2016

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Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.

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Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy

Cited by 37 publications

References 30 publications

Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy

Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

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