Sarcopenia and recovery from Disuse-Induced Atrophy

The aging process is associated with a progressive decline in motor function that has a major impact on the
ability to maintain an independent lifestyle; contributing to the frailty and loss of mobility observed in older
adults. Aging is also associated with a reduced capacity to respond to growth cues derived from activities
such as resistance exercise and return to weight bearing following inactivity or injury. An inability to respond
to mechanical loading or to restore muscle size following extended periods of bed rest or inactivity
accelerates the progression of sarcopenia and contributes to the loss of functional mobility, independence
and the onset of frailty. The proposed research is of particular relevance to the Veteran’s Administration
since a significant number of patients within the system will suffer skeletal muscle atrophy as a
consequence of bed rest, immobilization, or neural trauma. Further, the effects of muscle atrophy are more
debilitating with age resulting in longer hospital stays, a decrease in mobility and independence, an increase
in falls, and long-term disability. Since the population of older veterans is rising, this issue represents a
growing medical and monetary concern for the VA. Thus, the long-term objective of the research outlined in
this proposal is to address an important unmet clinical need through the development of effective therapies
for the enhancement of muscle recovery following atrophy. Based on our recent findings, we hypothesize
that the lack of functional recovery following disuse-induced atrophy in aged animals is related, in part, to an
increase in neuromuscular junction impairment during disuse that worsens upon reloading. Recent studies
suggest that diet supplementation with long-chain omega-3 fatty acids has benefits to muscle mass and
force output, however, further study is needed. It is the objective of this proposal to test the ability of dietary
supplementation with fish oil to prevent the loss of muscle mass and function with age and enhance the
recovery of muscle mass and function following disuse-induced atrophy. These studies will use an animal
model that has outstanding translational application to humans: the Fischer Brown Norway F1 hybrid rat
(FBNF1). Completion of the specific aims outlined in this proposal will provide data on whether fish oil is a
potential treatment for sarcopenia and/or can enhance the recovery of muscle mass and function from
disuse atrophy. The studies will also provide information on the mechanisms involved in sarcopenia and
age-associated loss of growth capacity. In specific aim 1 we will test the ability of fish oil supplementation to
enhance the recovery of muscle from atrophy induced by hindlimb unloading in old male FBNF1 rats. Old
rats will receive an 8-week loading dose of dietary fish oil supplementation prior to hindlimb unloading,
which will continue throughout the 14 days of unloading and 14 days of reloading. In specific aim 2 we will
determine if 9 months of dietary fish oil supplementation can prevent or attenuate the loss of muscle mass
and strength in male and female rats. Dietary supplementation will begin at 22 months of age in males and
20 months of age in females; ages at which significant loss of hind limb muscle mass and function are not
measurable. Rats will be euthanized at multiple time points between 22 and 31 months in males (20 to 29
months in females) to monitor the loss of muscle mass and strength and to examine potential molecular and
cellular mechanisms of sarcopenia and potential mechanisms of action of the fish oil treatment.

Grant Number: 5I01BX005626-04
NIH Institute/Center: VA
Principal Investigator: Sue Bodine