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Androgen depletion alters the diurnal patterns to signals that regulate autophagy in the limb skeletal muscle

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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.

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Funding

This work was supported by funds from Institute of Successful Longevity and Florida State University to BSG.

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  1. Department of Nutrition, Food and Exercise Science, Florida State University, 600 W. Cottage Avenue, Tallahassee, FL, 32306, USA

    Michael L. Rossetti & Bradley S. Gordon

  2. Department of Biomedical Sciences, Florida State University College of Medicine, 115 W Call Street, Tallahassee, FL, 32304, USA

    Robert J. Tomko Jr

  3. Institute of Sports Sciences and Medicine, Florida State University, 600 W. Cottage Ave, Tallahassee, FL, 32306, USA

    Bradley S. Gordon

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Rossetti, M.L., Tomko, R.J. & Gordon, B.S. Androgen depletion alters the diurnal patterns to signals that regulate autophagy in the limb skeletal muscle. Mol Cell Biochem 476, 959–969 (2021). https://doi.org/10.1007/s11010-020-03963-9

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