Muscle Aging Phenotypes in Childhood Cancer Survivors

Childhood cancer survivors experience premature declines in muscle mass, strength, and physical function that contribute to morbidity and early mortality. The biological mechanisms driving these impairments are heterogeneous and poorly understood. This observational study aims to characterize distinct muscle health endotypes in adult survivors of childhood cancer using advanced imaging, neuromuscular testing, and functional assessment. Survivors with reduced muscle health and community controls will undergo multimodal magnetic resonance imaging and spectroscopy, nerve conduction studies, surface electromyography, body composition assessment, and physical performance testing during a single study visit integrated into an ongoing cohort evaluation. Identifying mechanistic endotypes of impaired muscle health will support development of targeted interventions to preserve function and improve long-term outcomes in childhood cancer survivors.

Primary Objective:

- Characterize reduced muscle health endotypes in childhood cancer survivors.

Secondary Objective:

- Identify specific treatment and lifestyle related risk factors for each reduced muscle health endotype.

Exploratory Objective:

- Host germline genetics will be associated with specific muscle endotypes.

Study Overview

• Status: Not yet recruiting
• Conditions: Muscle Weakness; Sarcopenia; Low Muscle Mass
• Intervention / Treatment: Other: Multimodal Muscle Imaging and Functional Assessment; Other: Multimodal Muscle Imaging and Neuromuscular Assessment; Other: Comprehensive Muscle Phenotyping; Other: Integrated Neuromuscular and Imaging Evaluation

Detailed Description

Survivors of childhood cancer are at increased risk for early-onset frailty characterized by low lean mass, muscle weakness, and impaired physical function. Prior studies in the St. Jude Lifetime Cohort (SJLIFE) demonstrate that the prevalence of these impairments increases with age and is associated with a significantly higher risk of mortality. Traditional lifestyle and resistance training interventions have yielded only modest benefits, suggesting that superficially similar muscle phenotypes may be driven by distinct biological mechanisms.

Potential contributors to impaired muscle health in this population include peripheral nervous system dysfunction, altered motor unit activation, mitochondrial dysfunction, and muscle fat infiltration, resulting from cancer therapies, chronic health conditions, and lifestyle factors. Advanced imaging and neuromuscular phenotyping provide an opportunity to define distinct mechanistic "endotypes" that underlie reduced muscle health and to inform future precision interventions.

• Study Type: Observational
• Enrollment (Estimated): 533

Contacts and Locations

• Study Contact: Name: Kirsten Ness, PhD; Phone Number: 888-226-4343; Email: referralinfo@stjude.org

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
      • Principal Investigator: Kirsten Ness, PhD
      • Contact: Kirsten Ness, PhD; Phone Number: 888-226-4343; Email: referralinfo@stjude.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population includes adults aged 18 years or older enrolled in the St. Jude Lifetime Cohort (SJLIFE) who are childhood cancer survivors and community control participants without a cancer history. Eligible survivors are at least five years from primary cancer diagnosis and have reduced muscle mass and/or muscle strength based on age- and sex-specific z-scores. Survivors are categorized by prior exposure to peripheral neurotoxic cancer therapies. Community controls are frequency-matched by age and sex. All participants complete neuromuscular, imaging, and physical function assessments during a single study visit.

Description

Inclusion Criteria:

• Age 18 years old or older at time of consent and enrolled in SJLIFE.
• Participant (100 per group for a total of 400) is/has:
• Group 1: No cancer history
• Group 2: Age and sex specific relative lean mass z-score of less than -0.5 OR age and sex specific hand grip or isokinetic (60 degrees/sec) quadriceps strength z-score of <-0.5 AND exposure to a peripheral neurotoxin.
• Group 3: Age and sex specific relative lean mass z-score of less than -0.5 OR age and sex specific hand grip or isokinetic (60 degrees/sec) quadriceps strength z-score of <-0.5 AND NOT exposed to a peripheral neurotoxin.
• Group 4: Age and sex specific relative lean mass z-score of less than -0.5 AND age and sex specific hand grip strength or isokinetic (60 degrees/sec) quadriceps strength z-score of <-0.5 REGARDLESS of exposure status.
• Participant or legal guardian is able and willing to give informed consent.

Exclusion Criteria:

• Presence of implanted medical devices or metal that would interfere with MRI or MRS.
• Female Participant is pregnant.
• Body weight exceeding 300 pounds, due to MRI restrictions.
• Inability to lie flat on his/her back for 90 minutes or longer for MRI.
• Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Community Controls; Adults with no history of cancer recruited from the community or non-first-degree relatives of St. Jude patients.	Other: Multimodal Muscle Imaging and Functional Assessment; Participants undergo comprehensive muscle phenotyping, including magnetic resonance imaging (MRI) to assess muscle cross-sectional area and fat fraction; magnetic resonance spectroscopy (¹H MRS and ³¹P MRS) to evaluate skeletal muscle mitochondrial energetics; body composition assessment using dual energy X ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA); nerve conduction velocity testing; surface electromyography (EMG); and standardized physical performance testing.
Survivors With Low Lean Mass or Weakness and Peripheral Neurotoxin Exposure; Adult childhood cancer survivors with low lean mass and/or muscle weakness and documented exposure to peripheral neurotoxic therapies.	Other: Multimodal Muscle Imaging and Neuromuscular Assessment; Participants complete advanced neuromuscular and imaging assessments, including MRI-based evaluation of muscle structure and fat infiltration; magnetic resonance spectroscopy to assess mitochondrial oxidative metabolism; DXA and BIA for lean mass measurement; nerve conduction studies; surface electromyography during submaximal and maximal muscle activation; and physical function testing, performed during a single study visit.
Survivors With Low Lean Mass or Weakness Without Peripheral Neurotoxin Exposure; Adult childhood cancer survivors with low lean mass and/or muscle weakness and no history of exposure to peripheral neurotoxic therapies.	Other: Comprehensive Muscle Phenotyping; Participants undergo protocol-defined observational assessments including MRI and MRS of skeletal muscle, body composition analysis via DXA and BIA, neuromuscular testing with nerve conduction velocity and surface electromyography, and functional performance evaluations to characterize muscle health and underlying biological mechanisms.
Survivors With Low Lean Mass and Muscle Weakness (Regardless of Neurotoxin Exposure); Adult childhood cancer survivors meeting criteria for both low lean mass and muscle weakness, irrespective of treatment exposure.	Other: Integrated Neuromuscular and Imaging Evaluation; Participants receive integrated phenotyping of muscle health using multimodal MRI and MRS imaging, neuromuscular testing with EMG and nerve conduction velocity, body composition assessment, and standardized physical performance measures to identify muscle aging endotypes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nerve conduction velocity (NCV) at rest and Electromyography (EMG) during submaximal and maximal force generation	Nerve conduction velocity (NCV) of sural sensory and tibial motor nerves will be performed using electromyography with standard landmarks for electrode placement. Compound Muscle Action Potential (CMAP) and Sensory Nerve Action Potential (SNAP) amplitudes are measured from negative to positive peak, and velocities calculated based on onset latency. NCV testing at rest and EMG during submaximal and maximal force generation will allow us to characterize the impact of the peripheral nervous system and the motor unit on muscle health.	Baseline
Creatinine recovery post exercise with magnetic resonance imaging (MRI)	The plantar flexion motion is performed during the dynamic CrCEST MRI and 31P MRS acquisitions to provide a standardized in scanner exercise stimulus that perturbs skeletal muscle energy metabolism in the calf muscles. We will perform Cr-weighted CEST MRI to map calf muscle Cr recovery kinetics following plantar flexion exercise using an ergometer device. MATLAB scripts will be used for post-processing CEST data. 31P-MRS is performed with 1H/31P dual-tuned surface/volume coil. PCr is determined by fitting the signal intensity of PCr following plantar flexion exercise to a mono-exponential function. We will acquire a steady state 31P-MR spectra for phosphorylated metabolite quantification.	Baseline
Intramyocellular and extramyocellular fat fraction in muscle during magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS)	Multiparametric MRI, 1H-MRS and Fat fraction MRI will be performed. 1H-MRS is a unique tool for studies of lipid metabolism because it is the only noninvasive method that separately quantifies Intramyocellular and extramyocellular lipids (IMCL and EMCL). Fat fraction is a metric for fat accumulation in healthy muscle tissue because of perturbed fatty acid oxidation. Dixon MRI sequence will be used to measure intramuscular fat fraction in legs and abdomen. MATLAB scripts are used for post- processing Dixon data. We will perform multiparametric quantitative MRI (PMID: 40172709). 1H-MRS is performed on a Siemens 3T scanner using Point RESolved Spectroscopy (PRESS) sequence (PMID: 3326459). A water-suppressed 1H spectrum will be acquired from a voxel positioned in gastrocnemius and soleus muscles. 1H- MRS data will be processed using LCModel (PMID: 8139448).	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To identify specific treatment related risk factors for each reduced muscle health endotype.	Identify specific treatment exposures (e.g. vinca-alkaloids, platinum, anthracyclines, glucocorticoids, alkylators, radiation, surgical resection) will be associated with specific muscle endotypes. We will assess their treatment related exposures through medical record abstraction.	Baseline
To identify specific chronic disease related risk for each reduced muscle health endotype.	Identify chronic diseases (e.g. growth hormone deficiency, hypogonadism, hypothyroidism, cardiovascular disease, pulmonary dysfunction, ataxia, hemiplegia) will be associated with specific muscle endotypes. We will review previously documented chronic conditions. New onset chronic conditions are ascertained during the study visit.	Baseline
To identify specific lifestyle related risk for each reduced muscle health endotype.	Identify lifestyle-related risk factors (e.g. inactivity, smoking, low dietary protein intake) will be associated with specific muscle endotypes. We will measure muscle mass and strength as well as review current health habits during the study visit.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To identify host germline genetics associated with specific muscle endotypes.	Known population based polygenic risk scores (PRS) for hand grip strength, peripheral nervous system disease, metabolic disorders, and obesity will be associated with specific reduced muscle health phenotypes. For this study we will perform deep phenotyping of 300 survivors who have known deficits in muscle health to identify specific endotypes to target for future intervention. The 100 community controls will provide healthy norms to characterize each endotype.	Baseline

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Investigators: Principal Investigator: Kirsten Ness, PhD, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2030
• Study Completion (Estimated): May 1, 2031

Study Registration Dates

• First Submitted: March 27, 2026
• First Submitted That Met QC Criteria: April 8, 2026
• First Posted (Actual): April 15, 2026

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Childhood Cancer Survivors; Neuromuscular Function; Muscle Health; Adult Survivors of Childhood Cancer
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Manifestations; Pathologic Processes; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Muscle Weakness; Sarcopenia
• Other Study ID Numbers: MUSCLEMAP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
• IPD Sharing Time Frame: Data will be made available at the time of article publication.
• IPD Sharing Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No