Muscle type and fiber type specificity in muscle wasting
01 Oct 2013-The International Journal of Biochemistry & Cell Biology (Int J Biochem Cell Biol)-Vol. 45, Iss: 10, pp 2191-2199
TL;DR: The identification of the signaling pathways responsible for the differential response of muscles types and fiber types can lead to a better understanding of the pathogenesis of muscle wasting and to the design of therapeutic interventions appropriate for the specific disorders.
About: This article is published in The International Journal of Biochemistry & Cell Biology.The article was published on 2013-10-01. It has received 412 citations till now. The article focuses on the topics: Muscle atrophy & Muscle contracture.
Citations
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TL;DR: Engineering of electrically and chemically responsive, contractile human muscle tissues (‘myobundles’) using primary myogenic cells provide an enabling platform for predictive drug and toxicology screening and development of novel therapeutics for muscle-related disorders.
Abstract: Existing in vitro models of human skeletal muscle cannot recapitulate the organization and function of native muscle, limiting their use in physiological and pharmacological studies. Here, we demonstrate engineering of electrically and chemically responsive, contractile human muscle tissues ('myobundles') using primary myogenic cells. These biomimetic constructs exhibit aligned architecture, multinucleated and striated myofibers, and a Pax7(+) cell pool. They contract spontaneously and respond to electrical stimuli with twitch and tetanic contractions. Positive correlation between contractile force and GCaMP6-reported calcium responses enables non-invasive tracking of myobundle function and drug response. During culture, myobundles maintain functional acetylcholine receptors and structurally and functionally mature, evidenced by increased myofiber diameter and improved calcium handling and contractile strength. In response to diversely acting drugs, myobundles undergo dose-dependent hypertrophy or toxic myopathy similar to clinical outcomes. Human myobundles provide an enabling platform for predictive drug and toxicology screening and development of novel therapeutics for muscle-related disorders.
261 citations
Cites background from "Muscle type and fiber type specific..."
...changes or cell-matrix interactions that can be critical in different pathologies including muscle 64 dystrophies and wasting disorders(10)....
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...DOI: 10.7554/eLife.04885 2 of 14 Research article to investigate biochemical changes or cell–matrix interactions that can be critical in different pathologies including muscle dystrophies and wasting disorders (Ciciliot et al., 2013)....
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TL;DR: These findings suggest that some muscle diseases may be treated by shifting fiber type characteristics either from slow to fast, or fast to slow phenotypes, depending on the disease.
Abstract: Skeletal muscle fibers are classified into fiber types, in particular, slow twitch versus fast twitch. Muscle fiber types are generally defined by the particular myosin heavy chain isoforms that they express, but many other components contribute to a fiber's physiological characteristics. Skeletal muscle fiber type can have a profound impact on muscle diseases, including certain muscular dystrophies and sarcopenia, the aging-induced loss of muscle mass and strength. These findings suggest that some muscle diseases may be treated by shifting fiber type characteristics either from slow to fast, or fast to slow phenotypes, depending on the disease. Recent studies have begun to address which components of muscle fiber types mediate their susceptibility or resistance to muscle disease. However, for many diseases it remains largely unclear why certain fiber types are affected. A substantial body of work has revealed molecular pathways that regulate muscle fiber type plasticity and early developmental muscle fiber identity. For instance, recent studies have revealed many factors that regulate muscle fiber type through modulating the activity of the muscle regulatory transcription factor MYOD1. Future studies of muscle fiber type development in animal models will continue to enhance our understanding of factors and pathways that may provide therapeutic targets to treat muscle diseases. WIREs Dev Biol 2016, 5:518-534. doi: 10.1002/wdev.230 For further resources related to this article, please visit the WIREs website.
226 citations
Cites background from "Muscle type and fiber type specific..."
...Experiments in rat models have shown that denervation can cause fibertype specific atrophy but in different fiber types depending on the muscle group examined.(57) Taken together, the type of injury, the muscle group affected, and the time since injury or rest may all influence how specific muscle fiber types are affected....
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...Other examples of muscle wasting, such as cancer cachexia, fasting, and sepsis, show similar effects on muscle fiber type.(57) In these muscle disorders, type 2x fibers are particularly susceptible to atrophy; one possible reason for this increased susceptibility is their lower expression of PPARGC1A (also known as PGC-1α), relative to type 1 and 2A fibers....
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...The effects of acquired muscle wasting and metabolic disorders, in particular type 2 diabetes, obesity, and aging, on specific fiber types have been the subject of many excellent reviews.(1,2,56,57) Here we focus on studies of human subjects and summarize some of the major findings....
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TL;DR: Muscle size and architecture are both altered with advanced adult age and changes in myofibers include impairments in several physiological domains including muscle fiber activation, excitation-contraction coupling, actin-myosin cross-bridge interaction, energy production, and repair and regeneration.
Abstract: Aging has become an important topic for scientific research because life expectancy and the number of men and women in older age groups have increased dramatically in the last century. This is true in most countries of the world including the Republic of Korea and the United States. From a rehabilitation perspective, the most important associated issue is a progressive decline in functional capacity and independence. Sarcopenia is partly responsible for this decline. Many changes underlying the loss of muscle mass and force-generating capacity of skeletal muscle can be understood at the cellular and molecular levels. Muscle size and architecture are both altered with advanced adult age. Further, changes in myofibers include impairments in several physiological domains including muscle fiber activation, excitation-contraction coupling, actin-myosin cross-bridge interaction, energy production, and repair and regeneration. A thorough understanding of these alterations can lead to the design of improved preventative and rehabilitative interventions, such as personalized exercise training programs.
209 citations
TL;DR: To determine if mitochondrial degeneration precedes cancer‐induced muscle wasting in tumour‐bearing mice, a large number of mice were sacrificed to study the role of mitochondria in cancer cachexia.
Abstract: Background
Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer-related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer-induced muscle wasting in tumour-bearing mice.
Methods
First, weight-stable (MinStable) and cachectic (MinCC) ApcMin/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT-qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one-way ANOVA with Student–Newman–Kuels post hoc test.
Results
MinStable mice displayed ~50% lower Pgc-1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10-fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post-tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post-tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1–3 weeks post-tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour-bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting.
Conclusions
Functional mitochondrial degeneration is evident in LLC tumour-bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across ApcMin/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre-clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia.
172 citations
TL;DR: A general overview of skeletal muscle dysfunction in COPD is offered to highlight its relevance and magnitude to expert practitioners and scientists as well as to the average clinician dealing with patients with chronic respiratory diseases.
Abstract: Skeletal muscle dysfunction occurs in patients with chronic obstructive pulmonary disease (COPD) and affects both ventilatory and nonventilatory muscle groups. It represents a very important comorbidity that is associated with poor quality of life and reduced survival. It results from a complex combination of functional, metabolic, and anatomical alterations leading to suboptimal muscle work. Muscle atrophy, altered fiber type and metabolism, and chest wall remodeling, in the case of the respiratory muscles, are relevant etiological contributors to this process. Muscle dysfunction worsens during COPD exacerbations, rendering patients progressively less able to perform activities of daily living, and it is also associated with poor outcomes. Muscle recovery measures consisting of a combination of pulmonary rehabilitation, optimized nutrition, and other strategies are associated with better prognosis when administered in stable patients as well as after exacerbations. A deeper understanding of this process' pathophysiology and clinical relevance will facilitate the use of measures to alleviate its effects and potentially improve patients' outcomes. In this review, a general overview of skeletal muscle dysfunction in COPD is offered to highlight its relevance and magnitude to expert practitioners and scientists as well as to the average clinician dealing with patients with chronic respiratory diseases.
153 citations
Cites background from "Muscle type and fiber type specific..."
...phenomena: 1) Some fibers undergo selective atrophy, which causes an increase in the relative abundance of the unaffected type (20, 23); and 2) even in...
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...more efficient and the lower extremity muscles less efficient (23)....
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References
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TL;DR: Two genes encode ubiquitin ligases that are potential drug targets for the treatment of muscle atrophy, and mice deficient in either MAFbx orMuRF1 were found to be resistant to atrophy.
Abstract: Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.
3,174 citations
"Muscle type and fiber type specific..." refers background in this paper
..., 2004), which is induced before the onset of muscle atrophy and is necessary for the atrophy process (Bodine et al., 2001; Gomes et al., 2001)....
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...FoxO3 promotes the transcription of the ubiquitin ligases Atrogin1/MAFbx and MuRF1 (Sandri et al., 2004; Stitt et al., 2004), which is induced before the onset of muscle atrophy and is necessary for the atrophy process (Bodine et al., 2001; Gomes et al., 2001)....
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TL;DR: It is shown that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction.
2,657 citations
TL;DR: The results suggest that the regulation of autophagy is organ dependent and the role of Aut7/Apg8 is not restricted to the starvation response, and this transgenic mouse model is a useful tool to study mammalian autophagic regulation.
Abstract: Macroautophagy mediates the bulk degradation of cytoplasmic components. It accounts for the degradation of most long-lived proteins: cytoplasmic constituents, including organelles, are sequestered into autophagosomes, which subsequently fuse with lysosomes, where degradation occurs. Although the possible involvement of autophagy in homeostasis, development, cell death, and pathogenesis has been repeatedly pointed out, systematic in vivo analysis has not been performed in mammals, mainly because of a limitation of monitoring methods. To understand where and when autophagy occurs in vivo, we have generated transgenic mice systemically expressing GFP fused to LC3, which is a mammalian homologue of yeast Atg8 (Aut7/Apg8) and serves as a marker protein for autophagosomes. Fluorescence microscopic analyses revealed that autophagy is differently induced by nutrient starvation in most tissues. In some tissues, autophagy even occurs actively without starvation treatments. Our results suggest that the regulation of autophagy is organ dependent and the role of autophagy is not restricted to the starvation response. This transgenic mouse model is a useful tool to study mammalian autophagy.
2,238 citations
TL;DR: Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors.
Abstract: Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors. The relative proportion of the different fiber types varies strikingly between species, and in humans shows significant variability between individuals. Myosin heavy chain isoforms, whose complete inventory and expression pattern are now available, provide a useful marker for fiber types, both for the four major forms present in trunk and limb muscles and the minor forms present in head and neck muscles. However, muscle fiber diversity involves all functional muscle cell compartments, including membrane excitation, excitation-contraction coupling, contractile machinery, cytoskeleton scaffold, and energy supply systems. Variations within each compartment are limited by the need of matching fiber type properties between different compartments. Nerve activity is a major control mechanism of the fiber type profile, and multiple signaling pathways are implicated in activity-dependent changes of muscle fibers. The characterization of these pathways is raising increasing interest in clinical medicine, given the potentially beneficial effects of muscle fiber type switching in the prevention and treatment of metabolic diseases.
2,107 citations
TL;DR: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.
1,768 citations