Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls during hindlimb suspension

McMahon, Christopher D.; Popović, Ljiljana; Oldham, Jenny M.; Jeanplong, Ferenc; Smith, Harrison; Kambadur, Ravi; Sharma, Mridula; Maxwell, Linda; Bass, J. J.

doi:10.1152/ajpendo.00275.2002

Cited by 86 publications

(74 citation statements)

References 28 publications

(34 reference statements)

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“…It appears that mdx mice injected with myostatin antibodies for 3 mo showed an increase in muscle mass (11). Importantly, however, mice with muscle hypertrophy due to knockout of the myostatin gene show muscle atrophy that is equal to or greater than that on wild-type mice in response to unloading (68). This finding indicates that unloading-induced atrophy does not require myostatin.…”

Section: Myostatinmentioning

confidence: 96%

The molecular basis of skeletal muscle atrophy

Jackman¹,

Kandarian²

2004

American Journal of Physiology-Cell Physiology

826

708

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. The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol 287: C834 -C843, 2004; 10.1152/ajpcell.00579.2003.-Skeletal muscle atrophy attributable to muscular inactivity has significant adverse functional consequences. While the initiating physiological event leading to atrophy seems to be the loss of muscle tension and a good deal of the physiology of muscle atrophy has been characterized, little is known about the triggers or the molecular signaling events underlying this process. Decreases in protein synthesis and increases in protein degradation both have been shown to contribute to muscle protein loss due to disuse, and recent work has delineated elements of both synthetic and proteolytic processes underlying muscle atrophy. It is also becoming evident that interactions among known proteolytic pathways (ubiquitin-proteasome, lysosomal, and calpain) are involved in muscle proteolysis during atrophy. Factors such as TNF-␣, glucocorticoids, myostatin, and reactive oxygen species can induce muscle protein loss under specified conditions. Also, it is now apparent that the transcription factor NF-B is a key intracellular signal transducer in disuse atrophy. Transcriptional profiles of atrophying muscle show both up-and downregulation of various genes over time, thus providing further evidence that there are multiple concurrent processes involved in muscle atrophy. The purpose of this review is to synthesize our current understanding of the molecular regulation of muscle atrophy. We also discuss how ongoing work should uncover more about the molecular underpinnings of muscle wasting, particularly that due to disuse. protein synthesis; protein degradation; nuclear factor-B; disuse; unloading; cachexia OVERVIEW Skeletal muscle atrophy is a change that occurs in muscles of adult animals as a result of the conditions of disuse (e.g., immobilization, denervation, muscle unloading), aging, starvation, and a number of disease states (i.e., cachexia). Regardless of the inciting event, skeletal muscle atrophy is characterized by a decrease in protein content, fiber diameter, force production, and fatigue resistance. The different types of conditions producing atrophy imply different types of molecular triggers and signaling pathways for muscle wasting. This review focuses on our current knowledge of the molecules involved in disuse atrophy.Although the molecular aspects of atrophy have received increased attention in the literature, the detailed reviews on disuse atrophy are concerned with the characterization of morphological and physiological changes (12,20,90). With cachexia, there have been multiple reviews, each having a slightly different focus, that summarize work on putative triggers and signaling molecules and on details of the proteolytic processes governing this type of muscle wasting (37,38,57,58). There are no comprehensive reviews, however, on the molecular basis of disuse atrophy with an organized discussion on the whole process, from the potential triggers and signaling molecules to the fi...

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Section: Myostatinmentioning

confidence: 96%

The molecular basis of skeletal muscle atrophy

Jackman¹,

Kandarian²

2004

American Journal of Physiology-Cell Physiology

826

708

View full text Add to dashboard Cite

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“…38 Absence of myostatin expression in myostatin knockout mice did not prevent the loss of muscle mass after hindlimb suspension. On the contrary, these mice are more susceptible to unloading-induced skeletal muscle atrophy.…”

Section: Anabolic Activationmentioning

confidence: 99%

“…On the contrary, these mice are more susceptible to unloading-induced skeletal muscle atrophy. 38 In recent animal experiments, Heineke et al 39 showed that a heart-specific deletion of myostatin with an Nkx2.5-cre allele prevented skeletal muscle atrophy in heart failure. In consequence, they postulated that myocardial myostatin expression controls muscle atrophy in heart failure via elevated serum myostatin concentrations.…”

Section: Anabolic Activationmentioning

confidence: 99%

Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age

et al. 2012

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Background-Muscle wasting occurs in both chronic heart failure (CHF) and normal aging and contributes to exercise intolerance and increased morbidity/mortality. However, the molecular mechanisms of muscle atrophy in CHF and their interaction with aging are still largely unknown. We therefore measured the activation of the ubiquitin-proteasome system and the lysosomal pathway of intracellular proteolysis in muscle biopsies of CHF patients and healthy controls in two age strata and assessed the age-dependent effects of a 4-week endurance training program on the catabolic-anabolic balance. Methods and Results-Sixty CHF patients (30 patients aged Յ55 years, mean age 46Ϯ5 years; 30 patients aged Ն65 years, mean age 72Ϯ5 years) and 60 healthy controls (30 subjects aged Յ55 years, mean age 50Ϯ5 years; 30 subjects aged Ն65 years, mean age 72Ϯ4 years) were randomized to 4 weeks of supervised endurance training or to a control group. Before and after the intervention, vastus lateralis muscle biopsies were obtained. The expressions of cathepsin-L and the muscle-specific E3 ligases MuRF-1 and MAFbx were measured by real-time polymerase chain reaction and confirmed by Western blot. At baseline, MuRF-1 expression was significantly higher in CHF patients versus healthy controls (mRNA: 624Ϯ59 versus 401Ϯ25 relative units; Pϭ0.007). After 4 weeks of exercise training, MuRF-1 mRNA expression was reduced by Ϫ32.8% (Pϭ0.02) in CHF patients aged Յ55 years and by Ϫ37.0% (PϽ0.05) in CHF patients aged Ն65 years. Conclusions-MuRF-1, a component of the ubiquitin-proteasome system involved in muscle proteolysis, is increased in the skeletal muscle of patients with heart failure. Exercise training results in reduced MuRF-1 levels, suggesting that it blocks ubiquitin-proteasome system activation and does so in both younger and older CHF patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00176319.

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“…While it has been known for some time that the loss in muscle protein due to disuse results from decreases in protein synthesis and increases in protein degradation rates (2), we are just beginning to learn about the upstream triggers and signaling pathways that regulate the changes in these target systems that determine protein content. While myostatin (3,4) and glucocorticoids (5) have been studied for a role in atrophy, and both can induce atrophy in normal muscle, neither is required for disuse atrophy in vivo (5,6). Recent work suggests that inhibition of the Akt growth pathway in muscle may be involved in the progression of disuse atrophy.…”

Section: Introductionmentioning

confidence: 99%

Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy

Hunter¹,

Kandarian²

2004

J. Clin. Invest.

141

160

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The intracellular signals that mediate skeletal muscle protein loss and functional deficits due to muscular disuse are just beginning to be elucidated. Previously we showed that the activity of an NF-κB-dependent reporter gene was markedly increased in unloaded muscles, and p50 and Bcl-3 proteins were implicated in this induction. In the present study, mice with a knockout of the p105/p50 (Nfkb1) gene are shown to be resistant to the decrease in soleus fiber cross-sectional area that results from 10 days of hindlimb unloading. Furthermore, the marked unloading-induced activation of the NF-κB reporter gene in soleus muscles from WT mice was completely abolished in soleus muscles from Nfkb1 knockout mice. Knockout of the B cell lymphoma 3 (Bcl3) gene also showed an inhibition of fiber atrophy and an abolition of NF-κB reporter activity. With unloading, fast fibers from WT mice atrophied to a greater extent than slow fibers. Resistance to atrophy in both strains of knockout mice was demonstrated clearly in fast fibers, while slow fibers from only the Bcl3 -/-mice showed atrophy inhibition. The slow-to-fast shift in myosin isoform expression due to unloading was also abolished in both Nfkb1 and Bcl3 knockout mice. Like the soleus muscles, plantaris muscles from Nfkb1 -/-and Bcl3 -/-mice also showed inhibition of atrophy with unloading. Thus both the Nfkb1 and the Bcl3 genes are necessary for unloading-induced atrophy and the associated phenotype transition. IntroductionReduced muscular activity due to bed rest, limb immobilization, sedentary lifestyles, or space flight is a widespread phenomenon that leads to significant muscle atrophy, weakness, fatigue, and insulin resistance (reviewed in ref. 1). While it has been known for some time that the loss in muscle protein due to disuse results from decreases in protein synthesis and increases in protein degradation rates (2), we are just beginning to learn about the upstream triggers and signaling pathways that regulate the changes in these target systems that determine protein content. While myostatin (3, 4) and glucocorticoids (5) have been studied for a role in atrophy, and both can induce atrophy in normal muscle, neither is required for disuse atrophy in vivo (5, 6). Recent work suggests that inhibition of the Akt growth pathway in muscle may be involved in the progression of disuse atrophy. Proteins of the Akt cascade of kinases involved in growth control are dephosphorylated with unloading (7-9). This is consistent with the decrease in protein synthesis rate.Work from our laboratory has implicated additional regulatory molecules in unloading-induced muscle atrophy: the NF-κB and inhibitory κB (IκB) family of transcriptional regulators (10). We showed marked transactivation of injected NF-κB reporter plasmids in soleus muscles from non-weight-bearing (i.e., hindlimb-unloaded) rats. Gel-shift and immunoblot data using nuclear extracts of these muscles showed that likely NF-κB/IκB candidates for involvement in disuse atrophy were p50 and Bcl-3, but not p65. The cano...

show abstract

Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls during hindlimb suspension

Cited by 86 publications

References 28 publications

The molecular basis of skeletal muscle atrophy

The molecular basis of skeletal muscle atrophy

Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age

Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy

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