More than 35% of adults in the U.S. undergo chronic sleep restriction (SR) which is associated with multiple,
incompletely understood adverse health outcomes. Chronic SR is increasingly recognized as a risk factor for
bone loss, bone fractures, and osteoporosis. Night shift work and chronic SR in middle-age to older adults
imparts a similar risk of fracture as corticosteroid therapy. Our preliminary data in skeletally immature male
rats show that chronic SR results in marked osteopenia, decreased cancellous bone mass, and lower bone
mineral density—effects that are not fully reversible despite discontinuation of sleep restriction. The effects of
SR on bone health during adulthood are unknown and the implications for diseases of aging may be different
than for immature bone. The objective of the proposed research is to determine the mechanisms by which
chronic sleep deficiency impairs bone quality and integrity in aging. Our rat model uniquely enables us to
produce long-term SR under controlled conditions to allow age-related changes in bone to become manifest
in vivo. In Aim 1, we will test the hypothesis, supported by preliminary data, that chronic SR exposure after
attainment of skeletal maturity impairs bone remodeling, resulting in decreased bone quality and increased
fragility. Male and female rats will be studied under chronic SR or control conditions for 10 wk (approximately
equivalent to 7 human yr) until 13.5 mo of age. We predict that this chronic SR exposure predisposes to
accelerated bone loss both then and later in aging. Therefore, a second cohort will be aged with sleep ad
libitum for 12 wk after chronic SR (approximately equivalent to 8 human yr) until 17.5 mo of age to compare
their bone quality and integrity to age-matched controls. In Aim 2, we will test the hypothesis that sympathetic
nervous system (SNS) activation, which is a hallmark of chronic SR in adults, mediates abnormal bone
remodeling. We will evaluate the role of SNS activation by 1) directly removing neural innervation by surgical
unilateral hindlimb sympathectomy, with the contralateral hindlimb serving as a paired control, and 2)
systemically blocking β-adrenergic receptors (β-AR) that, in other experimental conditions, decreases bone
formation and increases bone resorption by actions on bone cells, osteoclastogenic factors, and metabolism.
Biomechanical testing of bone will provide functional assessments and will be complemented by structural
and cellular determinants of bone quality. Static and dynamic histomorphometry will determine the extent to
which bone formation, turnover, and resorption explain SR-induced abnormalities in remodeling. We will
elucidate cellular, hormonal, and molecular-mediated mechanisms in chronic SR effects on bone quality and
integrity. The studies are innovative because they are firsts in the fields of sleep science and bone metabolism
and employ novel interventions. These studies will define a biological role for chronic sleep restriction in bone
loss and fracture risk with aging and define the role of SNS activation in its pathogenesis. These studies are
important to public health because both SR and fracture are common and amenable to intervention.