Skeletal Muscle Apoptosis and Physical Performance; Oxidative RNA/DNA Damage and Repair in Aged Human Muscle

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT01644279
First received: July 5, 2012
Last updated: July 31, 2014
Last verified: July 2014
  Purpose

The age-related loss of muscle mass and strength, also termed sarcopenia, is a commonly recognized consequence of aging and has been associated with frailty, functional loss, hospitalization, and increased mortality among older people. Sarcopenia and its consequences have a considerable economic impact, since it has been estimated that the healthcare cost attributable to sarcopenia in the US in 2000 was $ 18.5 billions. Preclinical animal models strongly suggest that apoptosis, a programmed cell death, might play a prominent role in the age-related muscle wasting. In specific aim one, the investigators will assess the extent of muscle apoptosis in muscle biopsies obtained from the vastus lateralis muscle of young control subjects (ages 20-35) and high-performance and low-performance older subjects (age range 70-99 years). In specific aim 2, the investigators will investigate the role of Poly (ADP-ribose) polymerase 1 (PARP-1) and apoptosis-inducing factor (AIF) in the induction of skeletal muscle apoptosis. In specific aim 3, the investigators propose to investigate the contribution of the muscle energy deficit, due to the age-related mitochondrial dysfunction, in the development of muscle wasting. Finally, in specific aim 4, the investigators propose to reassess after four years physical performance, muscle mass and the extent of muscle apoptosis, in the high-performing participants, in order to correlate eventual decline in physical function, muscle mass and functional status, with changes in muscle apoptosis and in biochemical parameters in this very old population. Physical performance will be established according to the summary performance score obtained in the Short Form Physical Performance Battery (SPPB). In addition to the SPPB the investigators will also employ hand grip strength and knee extensor strength tests and the investigators will quantify muscle contractile area using 3D magnetic resonance imaging. Disability will be assessed using a self-report questionnaire. These studies will enhance our understanding of the biology and pathophysiology underlying the geriatric syndrome of sarcopenia and provide significant and novel insights that will enable us to identify new potential targets for interventions aimed at preventing and treating sarcopenia and functional impairment in older adults.


Condition
Sarcopenia

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Claude D. Pepper Older Americans Independence Center (OAIC); Skeletal Muscle Apoptosis and Physical Performance; Oxidative RNA/DNA Damage and Repair in Aged Human Muscle

Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Short Form Physical Performance Battery (SPPB) [ Time Frame: baseline ] [ Designated as safety issue: No ]
    The SPPB is composed by three subtasks: usual gait speed, standing balance and chair stand tests.

  • Cytochrome c oxidase activity [ Time Frame: baseline ] [ Designated as safety issue: No ]
    Cytochrome c oxidase (COX) activity measured in permeabilized fibers from muscle biopsy specimens.

  • Muscle strength [ Time Frame: baseline ] [ Designated as safety issue: No ]
    Muscle strength will be assessed by hand grip strength test and the isokinetic knee extensor test.

  • Quadriceps contractile area [ Time Frame: baseline ] [ Designated as safety issue: No ]
    3D magnetic resonance imaging (MRI) to precisely quantify the quadriceps contractile area

  • Peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) [ Time Frame: baseline ] [ Designated as safety issue: No ]
    Major regulator of mitochondrial content and oxidative metabolism in several tissues, including skeletal muscle; measured in muscle biopsy specimens.

  • Sirtuin 3 (SIRT3) [ Time Frame: baseline ] [ Designated as safety issue: No ]
    The induction of mitochondrial gene expression and biogenesis is largely controlled by the coordinated actions of various transcriptional and metabolic regulators including Sirtuin 3 (SIRT3); measured in muscle biopsy specimens.

  • Short Form Physical Performance Battery (SPPB) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    The SPPB is composed by three subtasks: usual gait speed, standing balance and chair stand tests.

  • Cytochrome c oxidase activity [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Cytochrome c oxidase (COX) activity measured in permeabilized fibers from muscle biopsy specimens.

  • Muscle strength [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Muscle strength will be assessed by hand grip strength test and the isokinetic knee extensor test.

  • Quadriceps contractile area [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    3D magnetic resonance imaging (MRI) to precisely quantify the quadriceps contractile area

  • Peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Major regulator of mitochondrial content and oxidative metabolism in several tissues, including skeletal muscle; measured in muscle biopsy specimens.

  • Sirtuin 3 (SIRT3) [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    The induction of mitochondrial gene expression and biogenesis is largely controlled by the coordinated actions of various transcriptional and metabolic regulators including Sirtuin 3 (SIRT3); measured in muscle biopsy specimens.


Biospecimen Retention:   Samples With DNA

Skeletal muscle biopsy; plasma, serum, urine.


Estimated Enrollment: 63
Study Start Date: March 2006
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts
Young
Young (age 20-35 years old)
Old high-functioning
Old high-functioning (age 70-99 years old)
Old low-functioning
Old low-functioning (age 70-99 years old)

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Young (age 20-35 years; N =20), old high-functioning, (age 70-99 years; N = 25), and old low-functioning (age 70-99 years; N = 20) subjects.

Criteria

Inclusion criteria. The following inclusion criteria will be adopted to select the study participants:

  • males and females aged 20-35 and 70-99 years
  • sedentary lifestyle (i.e., the subject has spent less than 20 minutes per week in the past 2 month performing structured physical activity, such as exercising at a gym and/or weight training)
  • willing and able to give informed consent.

Exclusion criteria:

  • history of smoking in the prior 12 months
  • active treatment for cancer or history of cancer in the past 3 years
  • congestive heart failure New York Heart Association (NYHA) Class III or IV
  • previous stroke with upper and/or lower extremities involvement within the last 6 months
  • peripheral vascular disease Fontaine Class III/IV
  • History of life-threatening cardiac arrhythmias, stroke, severe Parkinson's disease or severe neurological disorders likely to interfere with physical function
  • cognitive impairment (i.e., Mini-Mental State Examination (MMSE) ≤ 23)
  • renal disease requiring dialysis
  • lung disease requiring steroids
  • lower extremity amputation
  • severe osteoarthritis that interferes with physical function
  • Complicated diabetes
  • inflammatory diseases such as active rheumatoid arthritis, vasculitis, autoimmune disorders, and inflammatory bowel disease
  • life-threatening illnesses with an estimated life expectancy less than 1 year
  • history of drug or alcohol abuse
  • taking growth hormone (GH) and/or estrogen replacement therapy
  • Testosterone medication
  • Anticoagulant therapy
  • involved in active weight loss > 5 kg in prior 3 months
  • planning to relocate out of the study area in the next 4 years (ages 70-99 only)
  • pregnancy
  • SPPB score of 8-10
  • Lidocaine allergy
  • MRI exclusions, such as pregnancy, claustrophobia, heart pacemaker / defibrillator, heart valve prosthesis, aneurysm clip, metallic stent, neurostimulation system, cochlear implants or inner ear prosthesis, insulin pump or other infusion pump, metal slivers in the orbital area/eye socket

Temporary exclusion criteria:

  • recent bacterial infection (< 2 weeks)
  • acute febrile illness in prior 2 months
  • high blood pressure (i.e., BP ≥ 180/110 mm Hg) at the screening visit (subject will be referred to his/her physician and reevaluated after appropriated therapy being instituted)
  • major surgery or hip/knee replacement in the past 6 months

Assessment of disability. The uniform measure proposed to use for the assessment of disability will be a self-report disability questionnaire. This questionnaire was developed for the Fitness Arthritis in Seniors Trial (FAST) and since then has been widely used in intervention and observational studies (e.g. ADAPT, REACT-1, OASIS, CHAMP). The questionnaire is not specific to a certain disease and asks about perceived difficulties in general activities of daily living during the last month. Respondents answer for each of the items whether they experience 1) no difficulty, 2) a little difficulty, 3) some difficulty, 4) a lot of difficulty, 5) unable to do or, 6) did not do for other reasons. Answers can be averaged across the items in order to receive an indication of the overall perceived disability burden by a person.

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01644279

Locations
United States, Florida
University of Florida
Gainesville, Florida, United States, 32611
Sponsors and Collaborators
University of Florida
Investigators
Principal Investigator: Christiaan Leeuwenburgh, PhD University of Florida
  More Information

Additional Information:
Publications:
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT01644279     History of Changes
Other Study ID Numbers: 429-2005, 2P30AG028740
Study First Received: July 5, 2012
Last Updated: July 31, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by University of Florida:
aging
sarcopenia
mitochondria
skeletal muscle
apoptosis

Additional relevant MeSH terms:
Sarcopenia
Muscular Atrophy
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Atrophy
Pathological Conditions, Anatomical
Signs and Symptoms

ClinicalTrials.gov processed this record on September 18, 2014