Cessation of cyclic stretch induces atrophy of C2C12 myotubes

Soltow, Quinlyn A.; Zeanah, Elizabeth H.; Lira, Vitor A.; Criswell, David S.

doi:10.1016/j.bbrc.2013.03.048

Cited by 38 publications

(55 citation statements)

References 31 publications

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“…Recent studies have demonstrated that cyclic stretch of differentiated C2C12 myotubes for as little as 1 hour per day (12% at 0.7 Hz) increases myocyte size in as little as two days 8 . To streamline this model, we found that in preliminary studies that stretching cells similarly (15% at 1.0 Hz) could induce myocyte growth in 6 hours, which became the basis for the present study.…”

Section: 0 Discussionmentioning

confidence: 99%

“…To streamline this model, we found that in preliminary studies that stretching cells similarly (15% at 1.0 Hz) could induce myocyte growth in 6 hours, which became the basis for the present study. Cyclic stretch of C2C12 myotubes induces the release IGF-1 and AngII, which act as autocrine/paracrine stimulators of IGF-1 8 and Angiotensin II 15 signaling on the C2C12 cells themselves, inducing an increase in cell size. As myocyte hypertrophy represents the increase in newly synthesized sarcomeres, the significance of the observed IGF-1 induced protein synthesis (evidenced by increased p-Akt and p-GSK3beta, respectively) is clear.…”

Section: 0 Discussionmentioning

confidence: 99%

“…Three digital images per culture were captured. The images were analyzed for myotube length, diameter and area using ImageJ imaging software (NIH) as previously described 8 .…”

Section: 0 Materials and Methodsmentioning

confidence: 99%

“…Recent studies have modeled skeletal muscle disuse by using cyclic stretch of differentiated myotubes (C2C12), which mimics the loading pattern of mature skeletal muscle, followed by cessation of stretch 8 . The resulting atrophy mimicked disuse atrophy and allowed investigation of the underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Cessation of biomechanical stretch model of C2C12 cells models myocyte atrophy and anaplerotic changes in metabolism using non-targeted metabolomics analysis

Ilaiwy

Quintana

Bain

et al. 2016

The International Journal of Biochemistry & Cell Biology

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Studies of skeletal muscle disuse, either in patients on bed rest or experimentally in animals (immobilization), have demonstrated that decreased protein synthesis is common, with transient parallel increases in protein degradation. Muscle disuse atrophy involves a process of transition from slow to fast myosin fiber types. A shift toward glycolysis, decreased capacity for fat oxidation, and substrate accumulation in atrophied muscles have been reported, as has accommodation of the liver with an increased gluconeogenic capacity. Recent studies have modeled skeletal muscle disuse by using cyclic stretch of differentiated myotubes (C2C12), which mimics the loading pattern of mature skeletal muscle, followed by cessation of stretch. We utilized this model to determine the metabolic changes using non-targeted metabolomics analysis of the media. We identified increases in amino acids resulting from protein degradation (largely sarcomere) that occurs with muscle atrophy that are involved in feeding the Kreb’s cycle through anaplerosis. Specifically, we identified increased alanine/proline metabolism (significantly elevated proline, alanine, glutamine, and asparagine) and increased α-ketoglutaric acid, the proposed Kreb’s cycle intermediate being fed by the alanine/proline metabolic anaplerotic mechanism. Additionally, several unique pathways not clearly delineated in previous studies of muscle unloading were seen, including: 1) elevated keto-acids derived from branched chain amino aicds (i.e. 2-ketoleucine and 2-keovaline), which feed into a metabolic pathway supplying acetyl-CoA and 2-hydroxybutyrate (also significantly increased); and 2) elevated guanine, an intermediate of purine metabolism, was seen at 12 hours unloading. Given the interest in targeting different aspects of the ubiquitin proteasome system to inhibit protein degradation, this C2C12 system may allow the identification of direct and indirect alterations in metabolism due to anaplerosis or through other yet to be identified mechanisms using a non-targeted metabolomics approach.

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Section: 0 Discussionmentioning

confidence: 99%

Section: 0 Discussionmentioning

confidence: 99%

“…Three digital images per culture were captured. The images were analyzed for myotube length, diameter and area using ImageJ imaging software (NIH) as previously described 8 .…”

Section: 0 Materials and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cessation of biomechanical stretch model of C2C12 cells models myocyte atrophy and anaplerotic changes in metabolism using non-targeted metabolomics analysis

Ilaiwy

Quintana

Bain

et al. 2016

The International Journal of Biochemistry & Cell Biology

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“…Finally, to assess whether 4-PBA could improve the resilience of Plec -/-myotubes against mechanical strain, we exposed cells spread on flexible membranes to cyclic stretch and assessed their vulnerability by microscopically monitoring their substrate detachment rates (17,18). In this experiment, 51% of differentiated Plec -/-myotubes detached, compared with only 15% of their Plec +/+ counterparts.…”

Section: Phenotype Amelioration Through Chemical Chaperone 4-pba Treamentioning

confidence: 99%

Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle

Winter¹,

Staszewska²,

Mihailovska³

et al. 2014

J. Clin. Invest.

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The ubiquitously expressed multifunctional cytolinker protein plectin is essential for muscle fiber integrity and myofiber cytoarchitecture. Patients suffering from plectinopathy-associated epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and mice lacking plectin in skeletal muscle display pathological desmin-positive protein aggregation and misalignment of Z-disks, which are hallmarks of myofibrillar myopathies (MFMs). Here, we developed immortalized murine myoblast cell lines to examine the pathogenesis of plectinopathies at the molecular and single cell level. Plectin-deficient myotubes, derived from myoblasts, were fully functional and mirrored the pathological features of EBS-MD myofibers, including the presence of desmin-positive protein aggregates and a concurrent disarrangement of the myofibrillar apparatus. Using this cell model, we demonstrated that plectin deficiency leads to increased intermediate filament network and sarcomere dynamics, marked upregulation of HSPs, and reduced myotube resilience following mechanical stretch. Currently, no specific therapy or treatment is available to improve plectin-related or other forms of MFMs; therefore, we assessed the therapeutic potential of chemical chaperones to relieve plectinopathies. Treatment with 4-phenylbutyrate resulted in remarkable amelioration of the pathological phenotypes in plectin-deficient myotubes as well as in plectin-deficient mice. Together, these data demonstrate the biological relevance of the MFM cell model and suggest that this model has potential use for the development of therapeutic approaches for EBS-MD.

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Effects of External Stimulators on Engineered Skeletal Muscle Tissue Maturation

Mueller

Trujillo‐Miranda

Maier

et al. 2020

Adv Materials Inter

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Engineering functional skeletal muscle tissue is an ongoing challenge because of the complexity of the in vivo microenvironment and the various factors that contribute to the development and maintenance of the native tissue. However, the growing understanding of the natural skeletal muscle's microenvironment in vivo, as well as the ability to successfully reproduce these factors in vitro, are contributing to the formation of engineered skeletal muscle tissues (SMTs) with greater biomimetic structure and function. This review first summarizes the structure of skeletal muscle tissue. The role of various hydrogels, biomaterials, and scaffolds as building blocks of complex skeletal muscle structures is then explored. Additionally, the role of external stimuli and regulators that can be applied during in vitro culture that lead to the formation of SMT models with higher functionality is examined. These include various physical, biochemical, electrical, mechanical, and magnetic stimulations, as well as biological stimulation through coculture with fibroblasts, endothelial, or neuronal cells. Finally, examples of recently developed functional tissue models that have been developed for in vitro and in vivo applications and the future outlook for this field are discussed.

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Cessation of cyclic stretch induces atrophy of C2C12 myotubes

Cited by 38 publications

References 31 publications

Cessation of biomechanical stretch model of C2C12 cells models myocyte atrophy and anaplerotic changes in metabolism using non-targeted metabolomics analysis

Cessation of biomechanical stretch model of C2C12 cells models myocyte atrophy and anaplerotic changes in metabolism using non-targeted metabolomics analysis

Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle

Effects of External Stimulators on Engineered Skeletal Muscle Tissue Maturation

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