Identifying Therapeutic Targets of Accelerated Sarcopenia

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 known 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.

• Resistance exercise training (Behavioral), also known as RT: Supervised resistance exercise training, 3 times a week for 3 months
• Bed rest (Behavioral), also known as BR: Bed rest for 5 days, followed by standard rehabilitation for 2 days
• Intensive physical therapy (Behavioral), also known as PT: Intensive weight bearing PT, daily, during bed rest

Primary outcomes

• Leg Lean Mass [Change from baseline to up to 3 months]: Measurement of change in leg lean mass by DEXA

Secondary outcomes

• Knee Extension Strength [Change from baseline to up to 3 months]: Measurement of change in maximum strength by standard method

Other outcomes

• Amino Acid Transporter Expression [Change from baseline to up to 3 months]: Measurement of change in amino acid transporter expression
• Muscle Protein Synthesis [Change from baseline to up to 3 months]: Measurement of change in muscle protein synthesis by standard stable isotope methodology

Sex: All, ages: 60 Years to 85 Years, accepts healthy volunteers

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

Participant flow

Outcome results

• Leg Lean Mass (Primary), Mean, kg: Resistance Training in Type 2 Diabetes (T2DM) 0.35 +/- 0.74; Bed Rest in Healthy Subjects, Low-dose Amino Acids (LAA) -0.55 +/- 0.42; Bed Rest in Healthy Subjects, High-dose Amino Acids (HAA) -0.80 +/- 0.44; Bed Rest in Type 2 Diabetes (T2DM), Low-dose Amino Acids (LAA) -0.44 +/- 0.32; Bed Rest in Type 2 Diabetes (T2DM), High-dose Amino Acids (HAA) -0.66 +/- 0.31; Bed Rest in Healthy Subjects, Physical Therapy (PT) -0.59 +/- 0.73; Bed Rest in Type 2 Diabetes (T2DM), Physical Therapy (PT) -0.40 +/- 0.34 (p <0.01)
• Knee Extension Strength (Secondary), Mean, Nm: Resistance Training in Type 2 Diabetes (T2DM) 3 +/- 11; Bed Rest in Healthy Subjects, Low-dose Amino Acids (LAA) -12 +/- 20; Bed Rest in Healthy Subjects, High-dose Amino Acids (HAA) -24 +/- 16; Bed Rest in Type 2 Diabetes (T2DM), Low-dose Amino Acids (LAA) -23 +/- 13; Bed Rest in Type 2 Diabetes (T2DM), High-dose Amino Acids (HAA) -30 +/- 14; Bed Rest in Healthy Subjects, Physical Therapy (PT) -14 +/- 9; Bed Rest in Type 2 Diabetes (T2DM), Physical Therapy (PT) -8 +/- 22 (p <0.01)
• Amino Acid Transporter Expression (Other pre specified)
• Muscle Protein Synthesis (Other pre specified)

Adverse events

Time frame: Adverse events were monitored from baseline through 1 week following completion of the intervention period.

Other adverse events by term

• Study Protocol: 15-0229 Study Protocol (PDF, 2019-02-04)
• Study Protocol and Statistical Analysis Plan: 17-0064 Study Protocol (PDF, 2023-01-25)

• Elena Volpi, MD, PhD, Principal investigator, UTMB

NIH grants: R01AG049611