Identifying Therapeutic Targets of Accelerated Sarcopenia
| Status: | Recruiting |
|---|---|
| Conditions: | Healthy Studies, Orthopedic, Diabetes |
| Therapuetic Areas: | Endocrinology, Orthopedics / Podiatry, Other |
| Healthy: | No |
| Age Range: | 60 - 80 |
| Updated: | 11/16/2018 |
| Start Date: | May 28, 2017 |
| End Date: | December 2022 |
| Contact: | Roxana M Hirst, MS, CCRP |
| Email: | rmhirst@utmb.edu |
| Phone: | (409)266-9641 |
The proposed research is designed to identify the mechanisms that can accelerate loss of
muscle size, strength and physical function in type 2 diabetes and with hospitalization in
older persons. About ⅓ of older Americans have type 2 diabetes, and about ⅓ of the
hospitalizations in the USA involve persons older than 65 year of age. The proposed research
is relevant to the part of NIH's mission that pertains to development of the fundamental
knowledge that will improve health and reduce the burdens of disability, because this work
will provide the fundamental evidence to identify new targets for the development of
innovative treatments to slow down muscle loss and disability in our aging society.
muscle size, strength and physical function in type 2 diabetes and with hospitalization in
older persons. About ⅓ of older Americans have type 2 diabetes, and about ⅓ of the
hospitalizations in the USA involve persons older than 65 year of age. The proposed research
is relevant to the part of NIH's mission that pertains to development of the fundamental
knowledge that will improve health and reduce the burdens of disability, because this work
will provide the fundamental evidence to identify new targets for the development of
innovative treatments to slow down muscle loss and disability in our aging society.
Sarcopenia is a major contributor to frailty and increases the risk of falls, physical
dependence, disability and mortality in older adults. It advances slowly with healthy aging.
However, diseases or other insults and injuries can accelerate sarcopenia and lead to
catastrophic declines in mobility and independence. For example, chronic diseases such as
Type 2 Diabetes Mellitus (T2DM) are associated with accelerated loss of muscle mass and
function in seniors; hospitalization with bed rest inactivity acutely accelerates sarcopenia.
What it is not know is how concurrent diseases, inactivity or other insults and injuries
accelerate sarcopenia in older adults. This knowledge gap hinders the development of
innovative, targeted treatments for this disabling condition. The objective of this research
is to examine the basic mechanisms that underlie accelerated sarcopenia in older adults and
identify potential targets for interventions. The central hypothesis is that a global and
fundamental mechanism of acute or chronic acceleration of sarcopenia is a reduction in
skeletal muscle amino acid transport, which decreases muscle protein anabolism, and can be
reversed by activation of the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1)
signaling with a non-amino acid stimulus, such as exercise. Amino acid transport is an active
process that controls intracellular amino acid availability and the activation of protein
synthesis in skeletal muscle. It is regulated by amino acid concentrations and non-amino acid
stimuli that activate mTORC1 signaling, such as resistance exercise and insulin.The central
hypothesis will be tested with the following specific aims: 1) Determine the effect of T2DM
on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 2)
Determine the effect of short-term bed rest inactivity on the sensitivity of skeletal muscle
amino acid transport to dietary amino acids. 3) Determine the effect of resistance exercise
on the sensitivity of amino acid transport to dietary amino acids in acute and chronic
accelerated sarcopenia induced by inactivity or T2DM. Amino acid transport and protein
metabolism in muscle will be measured using integrative molecular, imaging and stable isotope
methodologies, identifying specific upstream regulators involved in the anabolic resistance
of accelerated sarcopenia that can be targeted with novel treatments to reduce sarcopenia and
improve independence in older adults.
dependence, disability and mortality in older adults. It advances slowly with healthy aging.
However, diseases or other insults and injuries can accelerate sarcopenia and lead to
catastrophic declines in mobility and independence. For example, chronic diseases such as
Type 2 Diabetes Mellitus (T2DM) are associated with accelerated loss of muscle mass and
function in seniors; hospitalization with bed rest inactivity acutely accelerates sarcopenia.
What it is not know is how concurrent diseases, inactivity or other insults and injuries
accelerate sarcopenia in older adults. This knowledge gap hinders the development of
innovative, targeted treatments for this disabling condition. The objective of this research
is to examine the basic mechanisms that underlie accelerated sarcopenia in older adults and
identify potential targets for interventions. The central hypothesis is that a global and
fundamental mechanism of acute or chronic acceleration of sarcopenia is a reduction in
skeletal muscle amino acid transport, which decreases muscle protein anabolism, and can be
reversed by activation of the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1)
signaling with a non-amino acid stimulus, such as exercise. Amino acid transport is an active
process that controls intracellular amino acid availability and the activation of protein
synthesis in skeletal muscle. It is regulated by amino acid concentrations and non-amino acid
stimuli that activate mTORC1 signaling, such as resistance exercise and insulin.The central
hypothesis will be tested with the following specific aims: 1) Determine the effect of T2DM
on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 2)
Determine the effect of short-term bed rest inactivity on the sensitivity of skeletal muscle
amino acid transport to dietary amino acids. 3) Determine the effect of resistance exercise
on the sensitivity of amino acid transport to dietary amino acids in acute and chronic
accelerated sarcopenia induced by inactivity or T2DM. Amino acid transport and protein
metabolism in muscle will be measured using integrative molecular, imaging and stable isotope
methodologies, identifying specific upstream regulators involved in the anabolic resistance
of accelerated sarcopenia that can be targeted with novel treatments to reduce sarcopenia and
improve independence in older adults.
Inclusion Criteria:
- Body mass index: <40 kg/sq meter
- Score ≥26 on the 30-item Mini Mental State Examination
- Stable body weight for at least 3 months
- Non-diabetic or with Type 2 Diabetes Mellitus
Exclusion Criteria:
- Pre-diabetes per American Diabetes Association criteria
- Insulin therapy, significant diabetic complications, or A1c>8%
- Impairment in Activities of Daily Living
- >2 falls/year
- weight loss >5% in the past 6 months
- Exercise training (≥2 sessions/week) or ≥10,000 steps/day
- Significant cardiovascular, liver, renal, blood, or respiratory disease
- Active cancer or infection
- Recent (within 3 months) treatment with anabolic steroids, systemic corticosteroids or
estrogen.
- Alcohol or drug abuse
We found this trial at
1
site
Galveston, Texas 77555
Principal Investigator: Elena Volpi, MD, PhD
Phone: 409-266-9641
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