Castration induces satellite cell activation that contributes to skeletal muscle maintenance

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.

Prepubertal skeletal muscle growth requires Pax7-expressing satellite cell-derived myonuclear contribution

“…Therefore, a decrease in the contribution of SC-derived progenitors to skeletal muscle growth is likely to be linked to the induction of sex hormones and regulation of Notch signaling. Indeed, castration of adult mice leads to disruption of SC quiescence and an increased requirement for SC-derived progenitor-mediated skeletal muscle maintenance ( Klose et al, 2018 ).…”

“…S9 " type="url"/> ). Similar to SC depletion in aging and androgen-deprived skeletal muscles, NMJ disruptions upon prepubertal SC depletion may require a longer period of time to appear ( Klose et al, 2018 ; Liu et al, 2017 ). Alternatively, the timing of SC depletion may be a factor.…”

“…In adult skeletal muscle, SCs reside at the interface between the myofiber and basal lamina, primarily in a quiescent state. However, in response to degenerative myofiber injury, denervation, or other triggers, SCs can be activated to participate in programs of repair or regeneration ( Klose et al, 2018 ; Liu et al, 2017 , 2015 ; Paris et al, 2016 ; Sambasivan et al, 2011 ). Various groups, through the use of either specific depletion of Pax7-expressing SCs or disruption of Pax7 expression, have demonstrated the indispensable nature of SCs in myofiber regeneration, repair and maintenance ( Egner et al, 2016 ; Fry et al, 2014 ; Gunther et al, 2013 ; Klose et al, 2018 ; Lepper et al, 2011 ; Liu et al, 2017 , 2015 ; Murphy et al, 2011 ; Relaix and Zammit, 2012 ; von Maltzahn et al, 2013 ).…”

Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopenia

“…muscle strength, reduced lean muscle mass, and increased adipose tissue. Castration specifically reduced muscle cross-sectional area and muscle absolute force production (17). Sarcopenia onset occurred 6 weeks after castration, and myostatin and activins were induced in muscles of adult male mice before the onset of strength loss (16).…”

More variety with the Journal of Cachexia, Sarcopenia and Muscle: JCSM Clinical Reports and JCSM Rapid Communications have both gone live

“…25 The first papers of JCSM Rapid Communications are now also online. 26,27 In the long run, we would think that JCSM Clinical Reports will be more clinically oriented as the title suggests and that JCSM Rapid Communications will be more oriented towards the basic science community of the wasting disorders field. We will all see whether it works out this way.…”