Castration induces satellite cell activation that contributes to skeletal muscle maintenance

Alanna Klose, Wenxuan Liu, Nicole Paris, Sophie Forman, John Krolewski, Kent Nastiuk, Joe V Chakkalakal

Abstract


Background: Sarcopenia, the age-related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. Decreased androgen signaling and deficits in the number and function of SCs are features of aging. Although androgen signaling is known to regulate skeletal muscle, the cellular basis for ADT-induced exacerbation of sarcopenia is unknown. Furthermore, the consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored. Methods: We examined SC fate in an androgen-deprived environment using immunofluorescence and fluorescence-activated cell sorting (FACS) with SC-specific markers in young castrated mice. To study the effects of androgen deprivation on SC function and skeletal muscle regenerative capacity, young castrated mice were subjected to experimental regenerative paradigms. SC-derived-cell contributions to skeletal muscle maintenance were examined in castrated Pax7CreER/+; ROSA26mTmG/+ mice. SCs were depleted in Pax7CreER/+; ROSA26DTA/+ mice to ascertain the consequences of SC ablation in sham and castrated skeletal muscles. Confocal immunofluorescence analysis of neuromuscular junctions (NMJs), and assessment of skeletal muscle physiology, contractile properties, and integrity were conducted. Results: Castration led to SC activation, however this did not result in a decline in SC function or skeletal muscle regenerative capacity. Surprisingly, castration induced SC-dependent maintenance of young skeletal muscle. The functional dependence of skeletal muscles on SCs in young castrated mice was demonstrated by an increase in SC-derived-cell fusion within skeletal muscle fibers. SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of NMJ-associated myonuclei in skeletal muscles from castrated mice. Conclusion: The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs. Considering the well-described age-related decline in SCs, the results in this study highlight the need to devise strategies that promote SC maintenance and activity to attenuate or reverse the progression of sarcopenia in elderly androgen-deprived individuals.


Full Text:

PDF

References


Judson RN, Zhang RH, Rossi FM. Tissue-resident mesenchymal stem/progenitor cells in skeletal muscle: collaborators or saboteurs? The FEBS journal 2013; 280: 4100-4108.

Paris ND, Soroka A, Klose A, et al. Smad4 restricts differentiation to promote expansion of satellite cell derived progenitors during skeletal muscle regeneration. eLife 2016; 5.

Liu W, Wei-LaPierre L, Klose A, et al. Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions. eLife 2015; 4.

Liu W, Klose A, Forman S, et al. Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration. eLife 2017; 6.

Relaix F, Zammit PS. Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage. Development 2012; 139: 2845-2856.

Chakkalakal JV, Jones KM, Basson MA, et al. The aged niche disrupts muscle stem cell quiescence. Nature 2012; 490: 355-360.

Mauro A. Satellite cell of skeletal muscle fibers. The Journal of biophysical and biochemical cytology 1961; 9: 493-495.

Brack AS, Rando TA. Tissue-specific stem cells: lessons from the skeletal muscle satellite cell. Cell stem cell 2012; 10: 504-514.

Chakkalakal JV, Christensen J, Xiang W, et al. Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state. Development 2014; 141: 1649-1659.

Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nature reviews Molecular cell biology 2013; 14: 329-340.

Mourikis P, Sambasivan R, Castel D, et al. A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem cells 2012; 30: 243-252.

Bjornson CR, Cheung TH, Liu L, et al. Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem cells 2012; 30: 232-242.

Sousa-Victor P, Gutarra S, Garcia-Prat L, et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 2014; 506: 316-321.

Rodgers JT, King KY, Brett JO, et al. mTORC1 controls the adaptive transition of quiescent stem cells from G to G. Nature 2014.

Alibhai SM, Breunis H, Timilshina N, et al. Impact of androgen-deprivation therapy on physical function and quality of life in men with nonmetastatic prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010; 28: 5038-5045.

Basaria S, Lieb J, 2nd, Tang AM, et al. Long-term effects of androgen deprivation therapy in prostate cancer patients. Clinical endocrinology 2002; 56: 779-786.

Thorsen L, Nilsen TS, Raastad T, et al. A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design. BMC cancer 2012; 12: 123.

Grossmann M, Zajac JD. Management of side effects of androgen deprivation therapy. Endocrinology and metabolism clinics of North America 2011; 40: 655-671, x.

Hara N, Ishizaki F, Saito T, et al. Decrease in lean body mass in men with prostate cancer receiving androgen deprivation therapy: mechanism and biomarkers. Urology 2013; 81: 376-380.

Haseen F, Murray LJ, Cardwell CR, et al. The effect of androgen deprivation therapy on body composition in men with prostate cancer: systematic review and meta-analysis. Journal of cancer survivorship : research and practice 2010; 4: 128-139.

Axell AM, MacLean HE, Plant DR, et al. Continuous testosterone administration prevents skeletal muscle atrophy and enhances resistance to fatigue in orchidectomized male mice. American journal of physiology Endocrinology and metabolism 2006; 291: E506-516.

Ibebunjo C, Eash JK, Li C, et al. Voluntary running, skeletal muscle gene expression, and signaling inversely regulated by orchidectomy and testosterone replacement. American journal of physiology Endocrinology and metabolism 2011; 300: E327-340.

Pan C, Singh S, Sahasrabudhe DM, et al. TGFbeta Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice. Endocrinology 2016; 157: 4461-4472.

Horstman AM, Dillon EL, Urban RJ, et al. The role of androgens and estrogens on healthy aging and longevity. The journals of gerontology Series A, Biological sciences and medical sciences 2012; 67: 1140-1152.

Sinha-Hikim I, Artaza J, Woodhouse L, et al. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. American journal of physiology Endocrinology and metabolism 2002; 283: E154-164.

Sinha-Hikim I, Roth SM, Lee MI, et al. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. American journal of physiology Endocrinology and metabolism 2003; 285: E197-205.

Serra C, Tangherlini F, Rudy S, et al. Testosterone improves the regeneration of old and young mouse skeletal muscle. The journals of gerontology Series A, Biological sciences and medical sciences 2013; 68: 17-26.

Kim JH, Han GC, Seo JY, et al. Sex hormones establish a reserve pool of adult muscle stem cells. Nature cell biology 2016.

Lubischer JL, Bebinger DM. Regulation of terminal Schwann cell number at the adult neuromuscular junction. The Journal of neuroscience : the official journal of the Society for Neuroscience 1999; 19: RC46.

Sousa-Victor P, Garcia-Prat L, Serrano AL, et al. Muscle stem cell aging: regulation and rejuvenation. Trends in endocrinology and metabolism: TEM 2015; 26: 287-296.

Cosgrove BD, Gilbert PM, Porpiglia E, et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nature medicine 2014; 20: 255-264.

Keefe AC, Lawson JA, Flygare SD, et al. Muscle stem cells contribute to myofibres in sedentary adult mice. Nature communications 2015; 6: 7087.

Murphy MM, Keefe AC, Lawson JA, et al. Transiently Active Wnt/beta-Catenin Signaling Is Not Required but Must Be Silenced for Stem Cell Function during Muscle Regeneration. Stem cell reports 2014; 3: 475-488.

Pawlikowski B, Pulliam C, Betta ND, et al. Pervasive satellite cell contribution to uninjured adult muscle fibers. Skeletal muscle 2015; 5: 42.

Murphy MM, Lawson JA, Mathew SJ, et al. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 2011; 138: 3625-3637.

Valdez G, Tapia JC, Kang H, et al. Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proceedings of the National Academy of Sciences of the United States of America 2010; 107: 14863-14868.

Sanes JR, Lichtman JW. Development of the vertebrate neuromuscular junction. Annual review of neuroscience 1999; 22: 389-442.

Zhang X, Xu R, Zhu B, et al. Syne-1 and Syne-2 play crucial roles in myonuclear anchorage and motor neuron innervation. Development 2007; 134: 901-908.

Mejat A, Decostre V, Li J, et al. Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy. The Journal of cell biology 2009; 184: 31-44.

Hippenmeyer S, Huber RM, Ladle DR, et al. ETS transcription factor Erm controls subsynaptic gene expression in skeletal muscles. Neuron 2007; 55: 726-740.

Grady RM, Starr DA, Ackerman GL, et al. Syne proteins anchor muscle nuclei at the neuromuscular junction. Proceedings of the National Academy of Sciences of the United States of America 2005; 102: 4359-4364.

Fry CS, Kirby TJ, Kosmac K, et al. Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy. Cell stem cell 2016.

Fry CS, Lee JD, Jackson JR, et al. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2014; 28: 1654-1665.

Brack AS, Bildsoe H, Hughes SM. Evidence that satellite cell decrement contributes to preferential decline in nuclear number from large fibres during murine age-related muscle atrophy. Journal of cell science 2005; 118: 4813-4821.

Shea KL, Xiang W, LaPorta VS, et al. Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration. Cell stem cell 2010; 6: 117-129.

Garcia-Prat L, Martinez-Vicente M, Perdiguero E, et al. Autophagy maintains stemness by preventing senescence. Nature 2016; 529: 37-42.

Balice-Gordon RJ, Breedlove SM, Bernstein S, et al. Neuromuscular junctions shrink and expand as muscle fiber size is manipulated: in vivo observations in the androgen-sensitive bulbocavernosus muscle of mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 1990; 10: 2660-2671.

Matthews GD, Huang CL, Sun L, et al. Translational musculoskeletal science: is sarcopenia the next clinical target after osteoporosis? Annals of the New York Academy of Sciences 2011; 1237: 95-105.

Li Y, Thompson WJ. Nerve terminal growth remodels neuromuscular synapses in mice following regeneration of the postsynaptic muscle fiber. The Journal of neuroscience : the official journal of the Society for Neuroscience 2011; 31: 13191-13203.

Banker BQ, Kelly SS, Robbins N. Neuromuscular transmission and correlative morphology in young and old mice. The Journal of physiology 1983; 339: 355-377.

Lyons PR, Slater CR. Structure and function of the neuromuscular junction in young adult mdx mice. Journal of neurocytology 1991; 20: 969-981.

Berchtold MW, Brinkmeier H, Muntener M. Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiological reviews 2000; 80: 1215-1265.

Brown R, Hynes-Allen A, Swan AJ, et al. Activity-dependent degeneration of axotomized neuromuscular synapses in Wld S mice. Neuroscience 2015; 290: 300-320.

Qaisar R, Renaud G, Morine K, et al. Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level? FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2012; 26: 1077-1085.

Amthor H, Macharia R, Navarrete R, et al. Lack of myostatin results in excessive muscle growth but impaired force generation. Proceedings of the National Academy of Sciences of the United States of America 2007; 104: 1835-1840.

Cooperberg MR, Grossfeld GD, Lubeck DP, et al. National practice patterns and time trends in androgen ablation for localized prostate cancer. Journal of the National Cancer Institute 2003; 95: 981-989.

Galvao DA, Taaffe DR, Spry N, et al. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010; 28: 340-347.

Hanson ED, Sheaff AK, Sood S, et al. Strength training induces muscle hypertrophy and functional gains in black prostate cancer patients despite androgen deprivation therapy. The journals of gerontology Series A, Biological sciences and medical sciences 2013; 68: 490-498.

Basaria S, Bhasin S. Targeting the skeletal muscle-metabolism axis in prostate-cancer therapy. The New England journal of medicine 2012; 367: 965-967.

Galvao DA, Taaffe DR, Cormie P, et al. Efficacy and safety of a modular multi-modal exercise program in prostate cancer patients with bone metastases: a randomized controlled trial. BMC cancer 2011; 11: 517.

Sanchis-Gomar F. The skeletal muscle-metabolism axis in prostate-cancer therapy. The New England journal of medicine 2012; 367: 2257-2258; author reply 2258.


Refbacks

  • There are currently no refbacks.