Androgen depletion alters the diurnal patterns to signals that regulate autophagy in the limb skeletal muscle
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Androgen depletion alters the diurnal patterns to signals that regulate autophagy in the limb skeletal muscle Michael L. Rossetti1 · Robert J. Tomko Jr2 · Bradley S. Gordon1,3 Received: 19 August 2020 / Accepted: 23 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Hypogonadism contributes to limb skeletal muscle atrophy by increasing rates of muscle protein breakdown. Androgen depletion increases markers of the autophagy protein breakdown pathway in the limb muscle that persist throughout the diurnal cycle. However, the regulatory signals underpinning the increase in autophagy markers remain ill-defined. The purpose of this study was to characterize changes to autophagy regulatory signals in the limb skeletal muscle following androgen depletion. Male mice were subjected to a castration surgery or a sham surgery as a control. Seven weeks post-surgery, a subset of mice from each group was sacrificed every 4 hr over a 24 hr period. Protein and mRNA from the Tibialis Anterior (TA) were subjected to Western blot and RT-PCR. Consistent with an overall increase in autophagy, the phosphorylation pattern of Uncoordinated Like Kinase 1 (ULK1) (Ser555) was elevated throughout the diurnal cycle in the TA of castrated mice. Factors that induce the progression of autophagy were also increased in the TA following androgen depletion including an increase in the phosphorylation of c-Jun N-terminal Kinase (JNK) (Thr183/Tyr185) and an increase in the ratio of BCL-2 Associated X (BAX) to B-cell lymphoma 2 (BCL-2). Moreover, we observed an increase in the protein expression pattern of p53 and the mRNA of the p53 target genes Cyclin-Dependent Kinase Inhibitor 1A (p21) and Growth Arrest and DNA Damage Alpha (Gadd45a), which are known to increase autophagy and induce muscle atrophy. These data characterize novel changes to autophagy regulatory signals in the limb skeletal muscle following androgen deprivation. Keywords Muscle atrophy · Hypogonadism · Protein degradation
Introduction Maintaining a critical amount of skeletal muscle mass is important to sustain physical function and reduce the risk of morbidity and mortality [1–4]. In males, testicular derived androgens are a key factor regulating muscle mass [5–7]. This mode of regulation is critical when endogenous production is compromised (termed hypogonadism) as muscle mass is decreased [8–10]. Atrophy of the limb muscles during * Bradley S. Gordon [email protected] 1
Department of Nutrition, Food and Exercise Science, Florida State University, 600 W. Cottage Avenue, Tallahassee, FL 32306, USA
2
Department of Biomedical Sciences, Florida State University College of Medicine, 115 W Call Street, Tallahassee, FL 32304, USA
3
Institute of Sports Sciences and Medicine, Florida State University, 600 W. Cottage Ave, Tallahassee, FL 32306, USA
hypogonadism is particularly important as they comprise most of the total muscle mass [11], and they are the primary contributors to physical function. Although androgen replacement therapy blun
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