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Prednisone is a type of glucocorticoid, a steroid used to treat inflammatory, allergic, and immunological disorders. It is a common treatment for myositis, a condition that causes muscle weakness and inflammation. However, there are concerns that the use of steroids like prednisone may cause muscle wasting, also known as myopathy, as a side effect. Studies have shown that glucocorticoids can cause muscle wasting in rats, and there is some evidence that this may also be the case in humans. This has been observed particularly in patients with asthma who use oral steroids, although the link is not yet fully understood.
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What You'll Learn
Proximal skeletal muscle wasting
Proximal skeletal muscles are those closest to the centre of the body, such as the muscles in the shoulders, upper arms, hips and thighs. Proximal myopathy presents as generalised muscle weakness commonly involving the muscles of the upper and/or lower limbs.
Proximal myopathy can be caused by toxins, long-term use of statins, corticosteroids, alcohol, SGLT2 inhibitors, COVID-19 vaccination, and antimalarials. It may also be observed in various idiopathic inflammatory myopathies (IIM) and hereditary/congenital myopathies.
Glucocorticoid-induced muscle wasting is a serious side effect of treatment with corticosteroids. Studies suggest that the upregulation of the transcription factors FOXO1 and C/EBPβ and the downregulation of MyoD and myogenin are involved in glucocorticoid-induced muscle wasting. In addition, glucocorticoid-induced hyperacetylation caused by increased expression of the nuclear cofactor p300 and its histone acetyl transferase activity, and decreased expression and activity of histone deacetylases (HDACs) play an important role in glucocorticoid-induced muscle proteolysis and wasting. Other mechanisms may also be involved in glucocorticoid-induced muscle wasting, including insulin resistance and store-operated calcium entry.
There is evidence that physical training improves muscle mass and strength in glucocorticoid-treated rats. Whether this is also true in humans is not known. However, there is evidence that steroid myopathy can be reversed by physical training in humans. Fifty days of isokinetic training in 12 patients increased the thigh muscle area, decreased the thigh fat area, and normalised the mean peak torque and total work output. The increase in peak torque was inversely correlated with the daily dose of prednisone. Thus, glucocorticoid-induced muscle wasting can be reversed by increasing physical activity in patients taking a low to moderate dose of prednisone.
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Reversing the effects with physical training
Steroid therapy is a common treatment for inflammatory, allergic, and immunological disorders. However, it is associated with adverse effects, including muscle wasting and myopathy, which can affect the proximal limbs and diaphragm. Proximal skeletal muscle wasting can cause a decrease in midthigh muscle area and an increase in midthigh fat-to-muscle ratio, leading to reduced muscle strength and function.
While there is no established rehabilitation program for steroid-induced myopathy in humans, physical training and exercise have shown promising results in animal studies. Japanese researchers found that even mild aerobic exercise can prevent the onset of steroid myopathy in rats. In this study, the group that received both exercise and steroid therapy had significantly larger muscle fiber areas than the group that received only steroid therapy.
Another study on rats with steroid myopathy found that treadmill exercise improved muscle fibers. Similarly, a study on humans taking low to moderate doses of prednisone found that 50 days of isokinetic training increased thigh muscle area, decreased thigh fat area, and normalized mean peak torque and total work output, thus reversing the effects of glucocorticoid-induced muscle wasting.
To reverse the effects of prednisone-induced muscle wasting, one study suggests that regular physical activity may help prevent protein wasting. In this study, healthy volunteers who engaged in a 4-week exercise program of jogging 2.5 miles four times a week experienced increased whole-body protein turnover and net protein retention when taking prednisone. These findings indicate that moderate exercise training can help prevent protein loss induced by prednisone.
While the direct impact of physical training on reversing prednisone-induced muscle wasting in humans requires further research, current evidence from animal studies and initial human trials suggests that physical activity and exercise can play a crucial role in mitigating and potentially reversing the muscle-wasting effects of prednisone and other steroids.
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Transcription factors and nuclear cofactors
In molecular biology, transcription factors (TFs) are proteins that bind to specific DNA sequences to control the transcription of genetic information from DNA to messenger RNA. TFs regulate gene expression by turning genes on and off, ensuring that they are expressed in the desired cells at the right time and in the right amount. Approximately 10% of genes in the human genome code for TFs, making them the largest family of human proteins.
TFs can bind to enhancer or promoter regions of DNA adjacent to the genes they regulate, and they recognize specific DNA motifs. TFs do not usually work alone; they form complex interactions with other TFs and proteins, which can play antagonistic roles in gene regulation. For gene transcription to occur, multiple TFs must bind to DNA regulatory sequences and recruit intermediary proteins such as cofactors.
Cofactors are proteins that modulate the effects of TFs. They are interchangeable between specific gene promoters, and their spatial conformation is determined by the protein complex occupying the promoter DNA and the amino acid sequence of the cofactor. Cofactors can be enzymatic or non-enzymatic, with non-enzymatic cofactors including TBP-associated factors (TAFs) and mediators (Meds).
The interaction between TFs and cofactors is dynamic and cell-specific, and it governs gene expression. Cofactors enhance the DNA-binding specificity of TFs and play a pivotal role in modulating TF activity by "reading" the chromatin landscape or preparing the site for binding. The integration of cofactors and TFs is critical to optimal TF activity, and mutations or translocations of cofactor genes can alter their interactions, potentially leading to the development of various disorders.
In physiological hematopoiesis, for example, finely tuned regulation of gene expression at each stage of development is required. This involves the production of hematopoietic stem cells (HSCs) and their differentiation into terminally differentiated cells. TFs and cofactors work together to ensure lineage-specific patterns of gene expression and the production of the correct proportions of individual cell lineages.
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Myogenin and muscle development
Glucocorticoid-induced myopathy is a common side effect of prednisone treatment, causing muscle wasting. While the mechanisms are not fully understood, studies suggest that the downregulation of myogenic transcription factors like MyoD and myogenin plays a role in glucocorticoid-induced muscle wasting.
Myogenin is a transcription factor that is essential for adult myofibre growth and muscle stem cell homeostasis. It is involved in muscle differentiation and development, regulating myocyte fusion during embryonic development. The continued expression of MyoD and the subsequent upregulation of myogenin are required to maintain the myogenic differentiation program. Myogenin helps keep muscle stem cells quiescent and controls their activation, with myogenin mutants displaying increased differentiation markers.
During muscle development, mononucleated myoblast cells fuse to form multinucleated myotubes, which are surrounded by a tubular arrangement of myofibrils (contractile organelles). Myogenin, along with MyoD, Myf5, and MRF4, are members of the Myogenic Regulatory Factor (MRF) family of transcription factors that regulate vertebrate muscle gene expression during early and adult myogenesis. The expression of these factors is induced by signals from the neural tube, with Myf5 expression observed first, followed by MyoD.
While the role of myogenin in adult myogenesis is less clear, studies in zebrafish suggest that it may be involved in maintaining muscle stem cell quiescence and controlling their activation. The downregulation of myogenin may contribute to glucocorticoid-induced muscle wasting, as observed in cultured C2C12 myotubes treated with dexamethasone, where a rapid decline in myogenin protein levels was noted.
In summary, myogenin is a key regulator of muscle development, growth, and repair. Its downregulation is implicated in glucocorticoid-induced muscle wasting, which is a side effect of prednisone treatment. Further research is needed to fully understand the mechanisms involved and explore potential strategies to prevent or treat muscle wasting in patients undergoing glucocorticoid therapy.
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Steroid myopathy as a side effect
Steroid myopathy is a well-known side effect of steroid therapy, which is a key treatment for inflammatory, allergic, and immunological disorders. Steroid therapy is considered the first-line therapy for myositis, but it is associated with muscle wasting and a loss of muscle strength.
Corticosteroid-induced myopathy is a highly prevalent toxic non-inflammatory myopathy that occurs as an adverse effect of prolonged oral or intravenous glucocorticoid use. It was first described in 1932 by Harvey Cushing as part of a constellation of symptoms seen in Cushing's syndrome. Cushing's syndrome is characterised by muscle weakness and atrophy without associated pain, and it predominantly affects pelvic girdle muscles.
Glucocorticoids have a direct catabolic effect on muscle, decreasing protein synthesis and increasing the rate of protein catabolism, leading to muscle atrophy. Studies suggest that glucocorticoid-induced upregulation of the transcription factors FOXO1 and C/EBPβ and downregulation of MyoD and myogenin are involved in glucocorticoid-induced muscle wasting. In addition, glucocorticoid-induced hyperacetylation caused by increased expression of the nuclear cofactor p300 and its histone acetyl transferase activity, and decreased expression and activity of histone deacetylases (HDACs) play an important role in glucocorticoid-induced muscle proteolysis and wasting. Other mechanisms contributing to glucocorticoid-induced muscle atrophy include insulin resistance and increased muscle calcium levels.
There is evidence that physical training improves muscle mass and strength in glucocorticoid-treated rats. Whether this is also true in humans is not known, but there is some evidence that increasing physical activity can reverse the effects of glucocorticoid-induced muscle wasting in patients taking a low to moderate dose of steroids.
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Frequently asked questions
Yes, treatment with glucocorticoids like prednisone causes wasting of proximal skeletal muscles.
Patients typically complain of a progressive inability to rise from chairs, climb stairs, and perform overhead activities.
Studies suggest that the expression and activity of FOXO transcription factors and C/EBPβ are upregulated by glucocorticoids, and that hyperacetylation caused by increased p300/HAT and decreased HDAC expression and activity may contribute to transcription factor activation.
There is evidence that physical training improves muscle mass and strength in glucocorticoid-treated rats. Whether this is also true in humans is not known.
