C-Protein in Fatigue and Aging

Study Overview
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Brief Summary
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This study is investigating changes to the proteins in skeletal muscle that contribute to reduced muscle size and muscle function that occurs with aging.

Detailed Description
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Age-related muscle atrophy and contractile dysfunction have been well described at the cellular level, but the molecular mechanisms that contribute to this dysfunction are poorly understood. Improved understanding of these mechanisms is critically important for the improvement of physical rehabilitation in older adults at risk for mobility impairment and physical disability. Our studies will pursue pre-clinical evidence that post translational modification of specific proteins in skeletal muscle lead to an aging phenotype in skeletal muscle that may unlock new strategies for improving physical function in older adults with physical frailty.

Official Title
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Skeletal Muscle Myosin Binding Protein C in Fatigue and Aging

Conditions
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Aging, Muscle Atrophy or Weakness, Sarcopenia in Elderly, Sarcopenia

Intervention / Treatment
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* Behavioral: Fatiguing Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults between the ages 18-35 or 65-80 years Healthy by self-report Willing to participate in all aspects of the study design including muscle biopsy, unilateral exercise, and physical activity monitoring Fluent in English (due to lack of translation services, it is not practical to conduct the study using a language other than English). Exclusion Criteria: Orthopaedic limitation (severe knee osteoarthritis, prior joint replacement, etc.). Volunteer has dementia or related mental issues that potentially put the subject at risk as determined by prior diagnosis. Volunteer has known untreated endocrine disease (hypo/hyper thyroidism, Addison's Disease or Cushing's syndrome, etc.) Volunteer has untreated/poorly-controlled hypertension (stage 2, per American College of Cardiology [>140/90 mmHg]). Volunteer has significant heart, liver, kidney or respiratory disease. Volunteer has diabetes (insulin dependent or non-insulin dependent). Volunteer has known coagulopathies. Volunteer has taken anabolic steroids in the prior six months. Volunteer has received treatment for cancer (other than effective Mohs Surgery for successful removal of basal cell or squamous cell carcinomas) Unexpected weight loss >5kg is last 12 months Volunteer is an active smoker or quit within the last year. Volunteer has known current alcohol or drug use disorder (AUD; defined as binge drinking of >4 days in the last month. Binge drinking is >5 drinks for men and >4 drinks for women, per occasion). Or, if a volunteer reports drinking in excess of low risk per NIAAA (>7 drinks/week for men and >3 drinks/day for women and >14 drinks/week and >4 drinks/day). Volunteer has a diagnosed neuromuscular disorder. Volunteer has allergy to lidocaine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fatigue<br>Volunteers will perform one-legged knee extension exercise until fatigue while seated on an ergometer. Volunteers will then undergo bilateral skeletal muscle biopsies of the vastus lateralis muscle in their thigh. | Behavioral: Fatiguing Exercise<br>* Volunteers will perform knee extension exercise of the dominant limb while seated in a chair designed for exercise of the knee extensor muscle group. The chair will be equipped with a lever arm, aligned with the axis of rotation of the knee and fixed to the distal shank, 2 centimeters proximal to the ankle joint. The lever arm will be instrumented to provide resistance and measure velocity. The volunteers will perform 3-5 maximum voluntary contractions (MVC) to determine peak torque. Once established, volunteers will rest for 5 minutes before initiating the fatigue protocol, whereby they will perform repeated MVC of the dominant limb against resistance equal to or less than 50% of MVC until range of motion cannot be maintained. Because the goal of this exercise is to uniformly fatigue the quadriceps muscle group, this exercise will be performed continuously. It is expected to take between 1 and 3 minutes to achieve the desired level of fatigue.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphorylation of myosin binding protein c (MyBP-C) | Muscle tissue is immediately frozen after biopsy. Liquid chromatography and high resolution mass spectrometry will be used to do a full analysis of the phosphorylation sites on MyBP-C isolated from the biopsied muscle tissue. | One week after the participant undergoes the biopsies. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle fiber Force | Ex vivo assessment of Force (mN) will be performed on muscle fibers and bundles isolated from fatigued and non-fatigued muscle biopsies. | Within three weeks of the intervention and biopsies. | 
| Muscle fiber Tension | Ex vivo assessment of Tension (kPa) will be performed on muscle fibers and bundles isolated from fatigued and non-fatigued muscle biopsies. | Within three weeks of the intervention and biopsies. | 
| Muscle fiber Velocity | Ex vivo assessment of Velocity (Lo/s) will be performed on muscle fibers and bundles isolated from fatigued and non-fatigued muscle biopsies. | Within three weeks of the intervention and biopsies. | 
| Muscle fiber Power | Ex vivo assessment of Power (w/L) will be performed on muscle fibers and bundles isolated from fatigued and non-fatigued muscle biopsies. | Within three weeks of the intervention and biopsies. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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muscle, aging, elderly, myosin, protein, sarcomere, exercise, function, atrophy, contractile, strength, balance, mobility, MyBP-C, fiber, biopsy, skeletal muscle, fatigue