scholarly journals Targeting muscle signaling pathways to minimize adverse effects of androgen deprivation

2015 ◽  
Vol 23 (1) ◽  
pp. R15-R26 ◽  
Author(s):  
Casey de Rooy ◽  
Mathis Grossmann ◽  
Jeffrey D Zajac ◽  
Ada S Cheung
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Skeletal Muscle ◽  
Adverse Effects ◽  
Muscle Mass ◽  
Muscle Growth ◽  
Androgen Deprivation ◽  
Muscle Histology ◽  
And Function ◽  
Protein Transcription

Androgen deprivation therapy (ADT) is a highly effective treatment used in ∼30% of men with prostate cancer. Adverse effects of ADT on muscle are significant with consistent losses in muscle mass. However, effects of ADT on muscle strength and physical function, of most relevance to the patient, are less well understood. This is in part due to the fact that muscle effects of ADT at the cellular, genetic and protein level, critical to the understanding of the pathophysiology of sarcopenia, have come into focus only recently. This review highlights the complexity of androgen-dependent signaling in muscle with an emphasis on recent findings in the regulation of muscle growth and muscle atrophy pathways. Furthermore, the effects of ADT and testosterone on skeletal muscle histology, gene expression and protein transcription are discussed. A better mechanistic understanding of the regulation of muscle mass and function by androgens should not only pave the way for developing targeted promyogenic interventions for men with prostate cancer receiving ADT but also may have wider implications for age-associated sarcopenia in the general population.

Testosterone suppression does not exacerbate disuse atrophy and impairs muscle recovery that is not rescued by high protein

2020 ◽  
Vol 129 (1) ◽  
pp. 5-16 ◽  
Author(s):  
Erik D. Hanson ◽  
Andrew C. Betik ◽  
Cara A. Timpani ◽  
John Tarle ◽  
Xinmei Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adverse Effects ◽  
Muscle Mass ◽  
Caloric Intake ◽  
Disuse Atrophy ◽  
Muscle Recovery ◽  
Testosterone Levels ◽  
Muscle Disuse ◽  
Low Testosterone ◽  
And Function

Low testosterone levels during skeletal muscle disuse did not worsen declines in muscle mass and function, although hypogonadism may attenuate recovery during subsequent reloading. Diets high in casein did not improve outcomes during immobilization or reloading. Practical strategies are needed that do not compromise caloric intake yet provide effective protein doses to augment these adverse effects.

scholarly journals Skeletal muscle wasting in chronic kidney disease: the emerging role of microRNAs

2019 ◽  
Vol 35 (9) ◽  
pp. 1469-1478 ◽  
Author(s):  
Kate A Robinson ◽  
Luke A Baker ◽  
Matthew P M Graham-Brown ◽  
Emma L Watson
Keyword(s):  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Exciting Field ◽  
Skeletal Muscle Wasting ◽  
And Function

Abstract Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. Evidence suggests that increasing skeletal muscle mass improves outcomes in CKD, making this a clinically important research focus. Despite extensive research, the pathogenesis of skeletal muscle wasting is not completely understood. It is widely recognized that microRNAs (miRNAs), a family of short non-coding RNAs, are pivotal in the regulation of skeletal muscle homoeostasis, with significant roles in regulating muscle growth, regeneration and metabolism. The abnormal expression of miRNAs in skeletal muscle during disease has been well described in cellular and animal models of muscle atrophy, and in recent years, the involvement of miRNAs in the regulation of muscle atrophy in CKD has been demonstrated. As this exciting field evolves, there is emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit the progression of CKD. In this article, we describe the pathophysiological mechanisms of muscle wasting and explore the contribution of miRNAs to the development of muscle wasting in CKD. We also discuss advances in our understanding of miRNAs in muscle–organ crosstalk and summarize miRNA-based therapeutics currently in clinical trials.

scholarly journals Alterations in intestinal microbiota diversity, composition, and function in patients with sarcopenia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lin Kang ◽  
Pengtao Li ◽  
Danyang Wang ◽  
Taihao Wang ◽  
Dong Hao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
16S Rrna ◽  
Intestinal Microbiota ◽  
Muscle Growth ◽  
Growth Function ◽  
16S Rrna Sequencing ◽  
Fecal Samples ◽  
Lipopolysaccharide Biosynthesis ◽  
Rrna Sequencing ◽  
And Function

Abstract16S rRNA sequencing of human fecal samples has been tremendously successful in identifying microbiome changes associated with both aging and disease. A number of studies have described microbial alterations corresponding to physical frailty and nursing home residence among aging individuals. A gut-muscle axis through which the microbiome influences skeletal muscle growth/function has been hypothesized. However, the microbiome has yet to be examined in sarcopenia. Here, we collected fecal samples of 60 healthy controls (CON) and 27 sarcopenic (Case)/possibly sarcopenic (preCase) individuals and analyzed the intestinal microbiota using 16S rRNA sequencing. We observed an overall reduction in microbial diversity in Case and preCase samples. The genera Lachnospira, Fusicantenibacter, Roseburia, Eubacterium, and Lachnoclostridium—known butyrate producers—were significantly less abundant in Case and preCase subjects while Lactobacillus was more abundant. Functional pathways underrepresented in Case subjects included numerous transporters and phenylalanine, tyrosine, and tryptophan biosynthesis suggesting that protein processing and nutrient transport may be impaired. In contrast, lipopolysaccharide biosynthesis was overrepresented in Case and PreCase subjects suggesting that sarcopenia is associated with a pro-inflammatory metagenome. These analyses demonstrate structural and functional alterations in the intestinal microbiota that may contribute to loss of skeletal muscle mass and function in sarcopenia.

Pharmacological Inhibition of Myostatin and Changes in Lean Body Mass and Lower Extremity Muscle Size in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

2014 ◽  
Vol 99 (10) ◽  
pp. E1967-E1975 ◽  
Author(s):  
Desmond Padhi ◽  
Celestia S. Higano ◽  
Neal D. Shore ◽  
Paul Sieber ◽  
Erik Rasmussen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lean Body Mass ◽  
Body Mass ◽  
Phase 1 ◽  
Muscle Growth ◽  
Androgen Deprivation ◽  
Negative Regulator ◽  
Muscle Size ◽  
Muscle Loss ◽  
Lower Extremity Muscle

Abstract Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. Objective: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer. Methods: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified. Results: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (±0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of −2.5% (±1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29. Conclusion: Four weekly sc doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.

scholarly journals Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer

Cancer ◽  
2009 ◽  
Vol 115 (11) ◽  
pp. 2388-2399 ◽  
Author(s):  
Lockwood G. Taylor ◽  
Steven E. Canfield ◽  
Xianglin L. Du
Keyword(s):  
Prostate Cancer ◽  
Adverse Effects ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation
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