TY - JOUR
T1 - Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age-related morphological changes
AU - Snyder-Warwick, Alison K.
AU - Satoh, Akiko
AU - Santosa, Katherine B.
AU - Imai, Shin ichiro
AU - Jablonka-Shariff, Albina
N1 - Publisher Copyright:
© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
PY - 2018/8
Y1 - 2018/8
N2 - Neuromuscular decline occurs with aging. The neuromuscular junction (NMJ), the interface between motor nerve and muscle, also undergoes age-related changes. Aging effects on the NMJ components—motor nerve terminal, acetylcholine receptors (AChRs), and nonmyelinating terminal Schwann cells (tSCs)—have not been comprehensively evaluated. Sirtuins delay mammalian aging and increase longevity. Increased hypothalamic Sirt1 expression results in more youthful physiology, but the relationship between NMJ morphology and hypothalamic Sirt1 was previously unknown. In wild-type mice, all NMJ components showed age-associated morphological changes with ~80% of NMJs displaying abnormalities by 17 months of age. Aged mice with brain-specific Sirt1 overexpression (BRASTO) had more youthful NMJ morphologic features compared to controls with increased tSC numbers, increased NMJ innervation, and increased numbers of normal AChRs. Sympathetic NMJ innervation was increased in BRASTO mice. In contrast, hypothalamic-specific Sirt1 knockdown led to tSC abnormalities, decreased tSC numbers, and more denervated endplates compared to controls. Our data suggest that hypothalamic Sirt1 functions to protect NMJs in skeletal muscle from age-related changes via sympathetic innervation.
AB - Neuromuscular decline occurs with aging. The neuromuscular junction (NMJ), the interface between motor nerve and muscle, also undergoes age-related changes. Aging effects on the NMJ components—motor nerve terminal, acetylcholine receptors (AChRs), and nonmyelinating terminal Schwann cells (tSCs)—have not been comprehensively evaluated. Sirtuins delay mammalian aging and increase longevity. Increased hypothalamic Sirt1 expression results in more youthful physiology, but the relationship between NMJ morphology and hypothalamic Sirt1 was previously unknown. In wild-type mice, all NMJ components showed age-associated morphological changes with ~80% of NMJs displaying abnormalities by 17 months of age. Aged mice with brain-specific Sirt1 overexpression (BRASTO) had more youthful NMJ morphologic features compared to controls with increased tSC numbers, increased NMJ innervation, and increased numbers of normal AChRs. Sympathetic NMJ innervation was increased in BRASTO mice. In contrast, hypothalamic-specific Sirt1 knockdown led to tSC abnormalities, decreased tSC numbers, and more denervated endplates compared to controls. Our data suggest that hypothalamic Sirt1 functions to protect NMJs in skeletal muscle from age-related changes via sympathetic innervation.
KW - NMJ
KW - Sirt1
KW - aging
KW - neuromuscular junction
KW - sirtuin
KW - terminal Schwann cell
UR - http://www.scopus.com/inward/record.url?scp=85047737401&partnerID=8YFLogxK
U2 - 10.1111/acel.12776
DO - 10.1111/acel.12776
M3 - Article
C2 - 29851253
AN - SCOPUS:85047737401
SN - 1474-9718
VL - 17
JO - Aging Cell
JF - Aging Cell
IS - 4
M1 - e12776
ER -