Abstract
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. 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. 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. 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.
Highlights
Castration led to satellite cells (SCs) activation, this did not result in a decline in SC function or skeletal muscle regenerative capacity
SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of neuromuscular junctions (NMJs)-associated myonuclei in skeletal muscles from castrated mice
The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs
Summary
Skeletal muscle possesses a remarkable capacity for regeneration, which is mediated by adult resident stem/progenitor cell populations that contribute to repair and maintenance [1,2,3,4]. Resident Pax7-expressing muscle stem cells (satellite cells (SCs)) function as an essential source of myonuclei for the early growth, regeneration and lifelong maintenance of skeletal muscle [2,3,4,5]. Disruption of quiescence, and the resulting inappropriate cell cycle entry, has been associated with depletion of the adult SC pool and loss of stem cell regenerative potential [6,10]. In contrast to the dysfunction of SC pool maintenance seen in aging or the loss of Notch signaling, other systemic signals can prime quiescent SCs to a poised state that enables a more efficient regenerative response [14]. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. The consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored
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