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

NCT01644279 | Completed DMC

• 2 other identifiers: 429-20052P30AG028740
• Study Type: observational
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Sarcopenia

Keywords

aging; sarcopenia; mitochondria; skeletal muscle; apoptosis

Outcome Measures

Primary Outcomes (12)

• Short Form Physical Performance Battery (SPPB)

  The SPPB is composed by three subtasks: usual gait speed, standing balance and chair stand tests.

  baseline

• Cytochrome c oxidase activity

  Cytochrome c oxidase (COX) activity measured in permeabilized fibers from muscle biopsy specimens.

  baseline

• Muscle strength

  Muscle strength will be assessed by hand grip strength test and the isokinetic knee extensor test.

  baseline

• Quadriceps contractile area

  3D magnetic resonance imaging (MRI) to precisely quantify the quadriceps contractile area

  baseline

• Peroxisome proliferator-activated receptor γ coactivator α (PGC-1α)

  Major regulator of mitochondrial content and oxidative metabolism in several tissues, including skeletal muscle; measured in muscle biopsy specimens.

  baseline

• Sirtuin 3 (SIRT3)

  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.

  baseline

• Short Form Physical Performance Battery (SPPB)

  The SPPB is composed by three subtasks: usual gait speed, standing balance and chair stand tests.

  4 years

• Cytochrome c oxidase activity

  Cytochrome c oxidase (COX) activity measured in permeabilized fibers from muscle biopsy specimens.

  4 years

• Muscle strength

  Muscle strength will be assessed by hand grip strength test and the isokinetic knee extensor test.

  4 years

• Quadriceps contractile area

  3D magnetic resonance imaging (MRI) to precisely quantify the quadriceps contractile area

  4 years

• Peroxisome proliferator-activated receptor γ coactivator α (PGC-1α)

  Major regulator of mitochondrial content and oxidative metabolism in several tissues, including skeletal muscle; measured in muscle biopsy specimens.

  4 years

• Sirtuin 3 (SIRT3)

  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.

  4 years

Study Arms (3)

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)

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Florida: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32611, United States

Location

Related Publications (5)

• Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LM, Aranda JM, Sandesara BD, Pahor M, Manini TM, Marzetti E, Leeuwenburgh C. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell. 2012 Oct;11(5):801-9. doi: 10.1111/j.1474-9726.2012.00844.x. Epub 2012 Jul 9.

  PMID: 22681576 RESULT

• Marzetti E, Lees HA, Manini TM, Buford TW, Aranda JM Jr, Calvani R, Capuani G, Marsiske M, Lott DJ, Vandenborne K, Bernabei R, Pahor M, Leeuwenburgh C, Wohlgemuth SE. Skeletal muscle apoptotic signaling predicts thigh muscle volume and gait speed in community-dwelling older persons: an exploratory study. PLoS One. 2012;7(2):e32829. doi: 10.1371/journal.pone.0032829. Epub 2012 Feb 28.

  PMID: 22389725 RESULT

• Buford TW, Lott DJ, Marzetti E, Wohlgemuth SE, Vandenborne K, Pahor M, Leeuwenburgh C, Manini TM. Age-related differences in lower extremity tissue compartments and associations with physical function in older adults. Exp Gerontol. 2012 Jan;47(1):38-44. doi: 10.1016/j.exger.2011.10.001. Epub 2011 Oct 12.

  PMID: 22015325 RESULT

• Marzetti E, Landi F, Marini F, Cesari M, Buford TW, Manini TM, Onder G, Pahor M, Bernabei R, Leeuwenburgh C, Calvani R. Patterns of circulating inflammatory biomarkers in older persons with varying levels of physical performance: a partial least squares-discriminant analysis approach. Front Med (Lausanne). 2014 Sep 1;1:27. doi: 10.3389/fmed.2014.00027. eCollection 2014.

  PMID: 25593902 RESULT

• Wawrzyniak NR, Joseph AM, Levin DG, Gundermann DM, Leeuwenburgh C, Sandesara B, Manini TM, Adhihetty PJ. Idiopathic chronic fatigue in older adults is linked to impaired mitochondrial content and biogenesis signaling in skeletal muscle. Oncotarget. 2016 Aug 16;7(33):52695-52709. doi: 10.18632/oncotarget.10685.

  PMID: 27447862 RESULT

Related Links

• University of Florida Claude D. Pepper Older Americans Independence Center (OAIC)

Biospecimen

Retention: SAMPLES WITH DNA

Skeletal muscle biopsy; plasma, serum, urine.

MeSH Terms

Conditions

Sarcopenia

Condition Hierarchy (Ancestors)

Muscular Atrophy; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Study Officials

• Christiaan Leeuwenburgh, PhD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 5, 2012
• First Posted: July 19, 2012
• Study Start: March 1, 2006
• Primary Completion: July 1, 2016
• Study Completion: July 1, 2016
• Last Updated: November 3, 2016

Record last verified: 2016-11

Locations

US (1)