Involvement of Muscle Mitochondrial Dysfunction in Frailty in Older Adults. Role of Exercise (MITOSTRENGTH)

This study aims to investigate the role of skeletal muscle mitochondrial dysfunction in the development of frailty in older adults and to evaluate whether a short-term, supervised resistance training intervention can improve skeletal muscle health and physical function.

Frailty is a common age-related condition associated with increased vulnerability to disability, hospitalisation, and loss of independence. It is characterised by features that may include weakness, fatigue, reduced physical activity, and slower walking speed. Mitochondrial dysfunction in skeletal muscle may contribute to the development of frailty and may be further influenced by chronic conditions such as type 2 diabetes mellitus (T2DM), which are associated with metabolic alterations, inflammation, oxidative stress, and insulin resistance.

Resistance training is an effective strategy to counteract age-related declines in muscle strength and physical function. However, the cellular and molecular mechanisms linking resistance training to improvements in mitochondrial function, skeletal muscle health, and resilience in older adults remain incompletely understood.

The study will include approximately 120 participants comprising older adults with T2DM, healthy older adults, and young healthy controls.

All participants will complete a 6-week supervised resistance training intervention, consisting of two sessions per week.

Assessments performed before and after the intervention will include body composition, muscle morphology, physical performance, muscle strength, frailty, and blood-based biomarkers. Peripheral blood mononuclear cells (PBMCs) will be used to assess mitochondrial function, and plasma samples will be used for proteomic profiling. Stool samples will be collected for analysis of gut microbiota.

A subset of participants will undergo skeletal muscle biopsies of the vastus lateralis at baseline and after the intervention. Muscle samples will be used to assess mitochondrial oxidative phosphorylation capacity, mitochondrial quality-control proteins, muscle fibre morphology, cell-type-specific transcriptomic profiles using single-nucleus RNA sequencing, and chromatin accessibility using ATAC-seq.

The study will provide an integrated assessment of the effects of resistance training on mitochondrial function, skeletal muscle biology, physical function, frailty, circulating biomarkers, and gut microbiota. These findings may help clarify the biological mechanisms through which resistance training influences muscle health and resilience during ageing and in older adults with T2DM.

Study Overview

• Status: Recruiting
• Conditions: Frail Elderly Syndrome; Diabetes Type 2; Functionality; Mitochondrial Function, Bioenergetics
• Intervention / Treatment: Other: Short-duration resistance training

Detailed Description

Background and Rationale:

Frailty is a multifactorial geriatric syndrome characterized by a decline in physiological reserves across multiple systems, leading to reduced resilience, weakness, and increased vulnerability to stressors such as acute illness, injury, or surgery. Clinically, frailty manifests as diminished strength, slowed mobility, exhaustion, and unintentional weight loss, often culminating in disability, hospitalization, and premature mortality. Among its core biological features, skeletal muscle deterioration, encompassing losses in muscle mass, contractile function, and regenerative capacity, plays a central role in the onset and progression of functional impairment and dependence in older adults.

At the cellular level, mitochondrial dysfunction has emerged as a key pathophysiological driver of frailty and sarcopenia. Mitochondria are essential for energy production, redox balance, and regulation of calcium homeostasis, apoptosis and inflammation. With aging, mitochondrial content, dynamics, and efficiency decline, leading to reduced ATP generation, increased reactive oxygen species (ROS) production, and accumulation of damaged mitochondrial DNA (mtDNA). These alterations compromise muscle bioenergetics and promote catabolic pathways that accelerate muscle atrophy. Moreover, defective mitophagy, an essential quality control process, leads to the persistence of dysfunctional organelles, perpetuating oxidative stress and inflammation.

Systemic metabolic disturbances further exacerbate these mitochondrial deficits. A chronic condition such as type 2 diabetes mellitus (T2DM) is frequently associated with frailty and share common mechanisms. Increased levels of pro-inflammatory cytokines (e.g., IL-6, TNF-α) and mitochondrial stress markers signal ongoing tissue damage and maladaptive stress responses. These interactions between metabolic dysregulation, inflammation, and mitochondrial dysfunction form a self-reinforcing cycle that underlies the molecular pathogenesis of frailty.

Exercise training, and particularly resistance exercise, is among the most potent non-pharmacological interventions to counteract frailty-related declines. Regular exercise improves muscle mass and strength, enhances glucose and lipid metabolism, and promotes mitochondrial biogenesis and function through activation of key molecular pathways. Furthermore, exercise induces the release of myokines that mediate intercellular communication between muscle and distant organs, influencing systemic metabolism, inflammation, and repair processes. However, despite well-established clinical benefits, the molecular and cellular mechanisms by which exercise remodels mitochondrial networks and restores metabolic homeostasis in frail or metabolically compromised individuals remain incompletely understood.

Elucidating how exercise modulates mitochondrial quality control, energy metabolism, and signaling pathways in the context of frailty could reveal new therapeutic targets to delay or reverse physiological decline. Integrating metabolic markers with molecular indicators of mitochondrial stress and muscle-derived factors offers a multidimensional approach to understanding the bioenergetic and inflammatory signatures of frailty and their reversibility through targeted interventions.

Study Objectives:

This project aims to:

1. Determine the contribution of skeletal muscle mitochondrial dysfunction to frailty in older adults, including those with T2DM.
2. Evaluate the effects of a 6-week supervised resistance training program on functional, molecular, and metabolic outcomes.
3. Characterize adaptations within the perimuscular interstitial microenvironment (fibroblasts, immune cells, vascular, neural and muscle stem cells as well as extracellular matrix components) that may mediate exercise-induced improvements in muscle health.

Through these objectives, the study seeks to integrate clinical, physiological, and molecular analyses to uncover mechanisms linking mitochondrial remodelling, aging, and exercise adaptation

Study Design:

This is a longitudinal, interventional study including 120 participants divided into three groups:

• Older adults with T2DM (≥65 years) - 40 participants
• Healthy older adults (≥65 years) - 40 participants
• Young healthy adults (19-35 years) - 40 participants (controls) All participants will complete baseline assessments, a 6-week supervised resistance training program, and post-intervention evaluations. Optional muscle biopsies will be obtained from participants who consent before and after training.

Intervention:

Participants will undergo a 6-week progressive resistance training program targeting the quadriceps muscles, consisting of two sessions per week (a total of 12 sessions), each lasting 30-50 minutes.

• Exercises include leg press and knee extension, progressing from submaximal to near-maximal effort as tolerated.
• Training intensity and progression will be individualised according to functional capacity.
• All sessions will be supervised by qualified exercise specialists to ensure safety and adherence.

This short, structured, and closely monitored training protocol was designed to be both safe and feasible for older adults with varying levels of frailty or diabetes.

Assessments and Procedures:

Baseline and Post-Intervention Evaluations:

Participants will undergo comprehensive testing before and after the exercise program, including:

• Blood sampling for metabolic, inflammatory, and aging biomarkers.
• Body composition analysis using DXA, ultrasound, and bioimpedance.
• Functional assessments of strength, balance, gait speed, and mobility.
• Stool sampling for gut microbiota composition.
• Optional muscle biopsies (quadriceps) under local anesthesia for mitochondrial and tissue-level analyses.

Muscle Biopsy Analyses

Muscle tissue samples will be used to examine:

• Mitochondrial function, oxidative stress, and biogenesis markers.
• Cellular and molecular characteristics of the perimuscular niche via single-nuclei and histological analyses.
• Changes in fibrosis, immune infiltration, vascular density, and extracellular matrix remodelling following exercise.

All biopsy procedures will be performed by trained clinicians following hospital safety protocols, with local anaesthesia and post-procedure monitoring.

Outcomes and Data Integration:

The study will generate a comprehensive dataset encompassing:

• Clinical and functional outcomes: muscle strength, mobility, balance, and composite frailty scores.
• Molecular and biochemical measures: mitochondrial respiration, oxidative stress and inflammatory markers, and pathways related to muscle regeneration.
• Circulating biomarkers: metabolic, inflammatory, and aging-related factors.
• Microbiome analyses: gut bacterial diversity and composition.
• Cross-sectional comparisons: differences across age and diabetes status.
• Longitudinal effects: pre- vs. post-intervention changes in functional and molecular endpoints.

This integrated approach will allow exploration of mechanistic links between exercise-induced mitochondrial remodelling, systemic inflammation, and functional improvements.

Safety Considerations:

The exercise program carries minimal risk and will be supervised at all times. Potential risks include mild muscle soreness or fatigue. Blood sampling may cause minor bruising or lightheadedness. Muscle biopsy, when performed, carries a small risk of pain, bleeding, or infection; all procedures will be conducted by trained clinical personnel with appropriate monitoring and follow-up.

Participants' safety will be prioritised throughout the study, with adherence logs, post-biopsy monitoring, and regular communication with healthcare providers.

Potential Benefits:

Participants may experience improvements in strength, balance, and mobility, as well as greater awareness of their health and functional capacity.

Beyond individual benefits, this project is expected to provide key insights into:

• The role of mitochondrial dysfunction and diabetes in age-related muscle decline.
• The cellular mechanisms underlying exercise-induced rejuvenation of skeletal muscle.
• Evidence-based strategies for designing personalised exercise programs to delay or prevent frailty.

Significance and Expected Impact:

By comparing diabetic and non-diabetic older adults with younger controls, this study will clarify the contribution of mitochondrial dysfunction and systemic metabolic stress to muscle aging and functional decline. It will also identify how short-term, supervised resistance training promotes beneficial adaptations within muscle fibers and their surrounding microenvironment.

The results will contribute to developing practical, safe, and effective interventions to maintain independence, improve quality of life, and reduce healthcare burden in aging populations. Ultimately, this project aims to bridge the gap between basic mitochondrial biology and translational geroscience, providing new insights into the prevention and management of frailty in older adults.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Maria Carmen Gómez Cabrera, Doctor in Physiology; Phone Number: +34-666871805; Email: carmen.gomez@uv.es

Study Locations

• Spain
  • Valencia, Spain, 46010
    • Recruiting
    • University of Valencia/Hospital Clínico Universitario de València,
    • Contact: Maria Carmen Gómez Cabrera, Doctor in Physiology; Phone Number: +34-666871805; Email: carmen.gomez@uv.es

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Inclusion criteria for young controls

  • Healthy young adults (18-35 years old)
  • Without any pathology or treatment

• Inclusion criteria for older controls

  • Healthy older adults (65 years or older)
  • Not currently enrolled in a resistance training program

• Inclusion criteria for cases

  • Age over 65 years
  • Diagnosis of frailty or robustness
  • Diagnosis of type 2 diabetes mellitus
  • Glycosylated hemoglobin (HbA1c) less than 9%
  • Treatment with metformin
  • Not currently enrolled in a resistance training program

Exclusion Criteria:

• Exclusion criteria for young controls

  • Pregnancy or suspected pregnancy
  • Body mass index greater than 35 kg/m2
  • Treatment within the last 30 days with oral corticosteroids
  • Edema or severe fluid regulation disorders that could alter bioimpedance results
  • Allergy to the local anesthetic mepivacaine
  • Prostheses, metal implants, or surgical staples lodinated or barium contrast for other imaging tests within the last 7 days

• Exclusion criteria for older controls

  • Decompensated and uncontrolled chronic diagnoses
  • Body mass index greater than 35 kg/m2
  • Treatment within the last 30 days with oral corticosteroids
  • Systemic diseases, active oncological disease, liver cirrhosis, untreated hypothyroidism, or severe chronic obstructive pulmonary disease (COPD).
  • Severe edema or fluid regulation disorders that could alter bioimpedance results
  • Allergy to the local anesthetic mepivacaine
  • Prostheses, metal implants, or surgical staples Iodinated or barium contrast for other imaging tests in the last 7 days

• Exclusion criteria for cases

  • Diagnosis of pre-frailty
  • Age over 80 years
  • Body mass index greater than 35 kg/m2
  • Time since onset of diabetes mellitus type 2 less than 10 years
  • Treatment with insulin
  • Treatment with allopurinol
  • Treatment with anticoagulant or antiplatelet drugs
  • Treatment within the last 30 days with oral corticosteroids
  • Advanced chronic complications of diabetes mellitus type 2 :

Renal failure (clearance <30 ml/min/m2) Macroalbuminuria greater than 200 mg/g Ischemic vascular diseases (acute myocardial infarction) Myocardial infarction, angina, stroke) Proliferative retinopathy or laser therapy Ulcerated diabetic foot or lower limb amputations, except for digital amputations

• Systemic diseases, active oncological disease, liver cirrhosis, untreated hypothyroidism, or severe chronic obstructive pulmonary disease
• Physical limitations in the lower limbs (acute or acute-on-chronic inflammatory processes, limited joint range of motion, chronic pain (visual analogue scale for pain > or = 4, etc.)
• Senile dementia
• Edema or severe fluid regulation disorders that may alter bioimpedance results
• Allergy to the local anesthetic mepivacaine
• Pacemaker, metallic prostheses or implants, surgical staples, and radiopaque tubes or catheters Iodinated or barium contrast for other imaging tests within the last 7 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group of healthy trained old people; Elderly patient without diagnosis of type 2 diabetes mellitus	Other: Short-duration resistance training; The exercise program will be personalized (based on functional status). This program will consist of 12 sessions spread over 6 weeks, two days a week, and will increase in duration (30-50 minutes). The lower body muscle group, targeting the quadriceps, will be trained with two exercises: leg press and quadriceps extension. The training intensity will be submaximal, progressing toward maximum. All patient groups, both controls and cases, will receive the same type of training.
Active Comparator: Group of type 2 diabetic trained old patients; Elderly patient diagnosed with type 2 diabetes mellitus	Other: Short-duration resistance training; The exercise program will be personalized (based on functional status). This program will consist of 12 sessions spread over 6 weeks, two days a week, and will increase in duration (30-50 minutes). The lower body muscle group, targeting the quadriceps, will be trained with two exercises: leg press and quadriceps extension. The training intensity will be submaximal, progressing toward maximum. All patient groups, both controls and cases, will receive the same type of training.
Active Comparator: Group of healthy trained young people; Young healthy control subjects	Other: Short-duration resistance training; The exercise program will be personalized (based on functional status). This program will consist of 12 sessions spread over 6 weeks, two days a week, and will increase in duration (30-50 minutes). The lower body muscle group, targeting the quadriceps, will be trained with two exercises: leg press and quadriceps extension. The training intensity will be submaximal, progressing toward maximum. All patient groups, both controls and cases, will receive the same type of training.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mitochondrial Oxidative Phosphorylation (OXPHOS) Capacity in Skeletal Muscle	Mitochondrial oxidative phosphorylation capacity will be assessed in permeabilised skeletal muscle fibre bundles obtained from vastus lateralis biopsies using high-resolution respirometry (Oxygraph-2k, Oroboros Instruments). OXPHOS capacity will be expressed as oxygen flux normalised to muscle tissue wet weight (pmol O₂·s-¹·mg-¹ wet tissue).	Baseline and after 6 weeks of supervised resistance training
Change in Mitochondrial Oxidative Phosphorylation (OXPHOS) Capacity in Peripheral Blood Mononuclear Cells (PBMCs)	Mitochondrial oxidative phosphorylation capacity will be assessed in permeabilised peripheral blood mononuclear cells (PBMCs) using high-resolution respirometry (Oxygraph-2k, Oroboros Instruments). OXPHOS capacity will be expressed as oxygen flux normalised to cell number (pmol O₂·s-¹·10⁶ cells-¹).	Baseline and after 6 weeks of supervised resistance training

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mitochondrial Quality Control Protein Expression in Skeletal Muscle	Protein expression of selected markers involved in mitochondrial dynamics, mitophagy, and biogenesis, including MFN1, MFN2, DRP1, PINK1, PARKIN, PGC-1α, and TFAM, will be assessed in vastus lateralis muscle biopsies by Western blot. Protein abundance will be quantified by densitometry, normalised to an appropriate loading control, and expressed as fold change relative to baseline.	Baseline and after 6 weeks of supervised resistance training
Change in Whole-Body Lean Mass	Whole-body lean mass will be assessed by dual-energy X-ray absorptiometry (DXA) and expressed in kilograms (kg).	Baseline and after 6 weeks of supervised resistance training
Change in Whole-Body Fat Mass	Whole-body fat mass will be assessed by dual-energy X-ray absorptiometry (DXA) and expressed in kilograms (kg).	Baseline and after 6 weeks of supervised resistance training
Change in 6-Minute Walk Test Distance	Functional exercise capacity will be assessed using the 6-Minute Walk Test (6MWT). The total distance walked during 6 minutes will be recorded in metres (m), with a greater distance indicating better functional exercise capacity.	Baseline and after 6 weeks of supervised resistance training
Change in Blood Glucose-6-Phosphate Dehydrogenase (G6PD) Activity	Glucose-6-phosphate dehydrogenase (G6PD) activity will be measured in blood as a systemic redox-related biomarker and expressed as units per gram of haemoglobin (U/g Hb).	Baseline and after 6 weeks of supervised resistance training
Change in Skeletal Muscle Cell-Type-Specific Transcriptomic Profiles	Single-nucleus RNA sequencing will be performed on vastus lateralis muscle biopsies to characterise cell-type-specific gene expression profiles in skeletal muscle. Transcript abundance will be quantified as normalised gene expression counts within identified cell populations.	Baseline and after 6 weeks of supervised resistance training
Change in Gut Microbiota Alpha Diversity	Gut microbiota alpha diversity will be assessed using the Shannon diversity index. The Shannon index is unitless, with higher values indicating greater microbial diversity.	Baseline and after 6 weeks of supervised resistance training
Change in Quadriceps Muscle Thickness	Quadriceps muscle thickness will be assessed by ultrasound and expressed in millimetres (mm).	Baseline and after 6 weeks of supervised resistance training
Change in Skeletal Muscle Fibre Cross-Sectional Area	Skeletal muscle fibre cross-sectional area will be assessed by histological analysis of vastus lateralis muscle biopsies and expressed in square micrometres (µm²).	Baseline and after 6 weeks of supervised resistance training
Change in Short Physical Performance Battery (SPPB) Score	Lower-extremity physical function will be assessed using the Short Physical Performance Battery (SPPB), which includes standing balance, usual gait speed, and repeated chair stands. The total score ranges from 0 to 12 points, with higher scores indicating better physical performance.	Baseline and after 6 weeks of supervised resistance training
Change in FallSkip Test Performance Time	Functional mobility and fall-related performance will be assessed using the FallSkip test. Time to complete the test will be recorded in seconds (s), with a shorter time indicating better performance.	Baseline and after 6 weeks of supervised resistance training
Change in Blood Malondialdehyde (MDA) Levels	Malondialdehyde (MDA) levels will be measured in blood as a marker of systemic lipid peroxidation and expressed in micromoles per litre (µmol/L).	Baseline and after 6 weeks of supervised resistance training
Change in Fried Frailty Phenotype Score	Frailty status will be assessed using the Fried Frailty Phenotype, based on five criteria: unintentional weight loss, self-reported exhaustion, low physical activity, slow walking speed, and weakness. The total score ranges from 0 to 5, with higher scores indicating greater frailty.	Baseline and after 6 weeks of supervised resistance training
Change in Frailty Classification Assessed by the Survey of Health, Ageing and Retirement in Europe Frailty Instrument (SHARE-FI)	Frailty will be assessed using the Survey of Health, Ageing and Retirement in Europe Frailty Instrument (SHARE-FI), which combines fatigue, loss of appetite, grip strength, functional difficulties, and physical activity. Participants will be classified as non-frail, pre-frail, or frail according to the SHARE-FI algorithm, with higher frailty categories indicating greater frailty.	Baseline and after 6 weeks of supervised resistance training
Change in Quadriceps Extension 3-Repetition Maximum (3RM)	Quadriceps muscle strength will be assessed using the 3-repetition maximum (3RM) during the quadriceps extension exercise. The maximum load successfully completed for three repetitions will be recorded in kilograms (kg), with higher values indicating greater muscle strength.	Baseline and after 6 weeks of supervised resistance training
Change in Skeletal Muscle Chromatin Accessibility Profiles Assessed by ATAC-seq	Chromatin accessibility will be assessed in skeletal muscle samples using Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq). Genome-wide chromatin accessibility profiles will be quantified using normalised accessibility signals across identified regulatory regions.	Baseline and after 6 weeks of supervised resistance training
Change in Plasma Proteomic Profiles	Plasma proteomic profiling will be performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to characterise changes in circulating protein abundance. Protein abundance will be quantified and expressed as normalised relative abundance values.	Baseline and after 6 weeks of supervised resistance training

Collaborators and Investigators

• Sponsor: Fundación para la Investigación del Hospital Clínico de Valencia
• Collaborators: University of Valencia; Ministerio de Ciencia e Innovación, Spain

Publications and helpful links

General Publications

• Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinkova E, Vandewoude M, Zamboni M; European Working Group on Sarcopenia in Older People. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010 Jul;39(4):412-23. doi: 10.1093/ageing/afq034. Epub 2010 Apr 13.
• Roberts HC, Denison HJ, Martin HJ, Patel HP, Syddall H, Cooper C, Sayer AA. A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach. Age Ageing. 2011 Jul;40(4):423-9. doi: 10.1093/ageing/afr051. Epub 2011 May 30.
• Pasini E, Corsetti G, Assanelli D, Testa C, Romano C, Dioguardi FS, Aquilani R. Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes. Minerva Med. 2019 Feb;110(1):3-11. doi: 10.23736/S0026-4806.18.05589-1.
• Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan 1;48(1):16-31. doi: 10.1093/ageing/afy169.
• Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. doi: 10.7326/0003-4819-150-9-200905050-00006.
• Ruiz Comellas A, Pera G, Baena Diez JM, Mundet Tuduri X, Alzamora Sas T, Elosua R, Toran Monserrat P, Heras A, Fores Raurell R, Fuste Gamisans M, Fabrega Camprubi M. [Validation of a Spanish Short Version of the Minnesota Leisure Time Physical Activity Questionnaire (VREM)]. Rev Esp Salud Publica. 2012 Oct;86(5):495-508. doi: 10.4321/S1135-57272012000500004. Spanish.
• Srere PA. An eclectic view of metabolic regulation: control of citrate synthase activity. Adv Enzyme Regul. 1970;9:221-33. doi: 10.1016/s0065-2571(71)80046-8. No abstract available.
• Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1768-73. doi: 10.1073/pnas.0510452103. Epub 2006 Jan 30.
• WALLER HD, LOHR GW, TABATABAI M. [Hemolysis and absence of glucose-6-phosphate dehydrogenase in erythrocytes; an enzyme abnormality of erythrocytes]. Klin Wochenschr. 1957 Oct 15;35(20):1022-7. doi: 10.1007/BF01488728. No abstract available. German.
• Bauerl C, Collado MC, Zuniga M, Blas E, Perez Martinez G. Changes in cecal microbiota and mucosal gene expression revealed new aspects of epizootic rabbit enteropathy. PLoS One. 2014 Aug 22;9(8):e105707. doi: 10.1371/journal.pone.0105707. eCollection 2014.
• Silva JSC, Seguro CS, Naves MMV. Gut microbiota and physical exercise in obesity and diabetes - A systematic review. Nutr Metab Cardiovasc Dis. 2022 Apr;32(4):863-877. doi: 10.1016/j.numecd.2022.01.023. Epub 2022 Jan 29.
• Perez-Ros P, Sanchis-Aguado MA, Dura-Gil JV, Martinez-Arnau FM, Belda-Lois JM. FallSkip device is a useful tool for fall risk assessment in sarcopenic older community people. Int J Older People Nurs. 2022 May;17(3):e12431. doi: 10.1111/opn.12431. Epub 2021 Oct 14.
• Hernandes NA, Wouters EF, Meijer K, Annegarn J, Pitta F, Spruit MA. Reproducibility of 6-minute walking test in patients with COPD. Eur Respir J. 2011 Aug;38(2):261-7. doi: 10.1183/09031936.00142010. Epub 2010 Dec 22.
• Chen X, Abbey S, Bharmal A, Harris S, Hudson E, Krinner L, Langan E, Maling A, Nijran J, Street H, Wooley C, Billeter R. Neurovascular structures in human vastus lateralis muscle and the ideal biopsy site. Scand J Med Sci Sports. 2019 Apr;29(4):504-514. doi: 10.1111/sms.13369. Epub 2019 Jan 27.

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2022
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2028

Study Registration Dates

• First Submitted: May 29, 2025
• First Submitted That Met QC Criteria: September 14, 2026
• First Posted (Actual): September 18, 2026

Study Record Updates

• Last Update Posted (Actual): September 18, 2026
• Last Update Submitted That Met QC Criteria: September 14, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Physical Function; Frailty; Mitochondrial function; Skeletal Muscle; Diabetes type 2
• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Frailty; Diabetes Mellitus, Type 2
• Other Study ID Numbers: MITOSTRENGTH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data (IPD) that underlie the results reported in this study will be shared, including data on baseline characteristics, frailty scores, functional assessments, mitochondrial, enzimatic and biochemical parameters. No identifiable information will be included.

The data will be available beginning 12 months following publication of the main results.

Access to the de-identified IPD will be provided to researchers whose proposed use of the data has been approved by an independent review committee. The requesting investigators must provide a methodologically sound proposal and agree to use the data for academic, non-commercial purposes only.

Data will be made available through an institutional repository or upon request.

• IPD Sharing Time Frame: Beginning 12 months after publication of the primary results and for a period of 5 years thereafter.
• IPD Sharing Access Criteria: Proposals should be directed to the principal investigator. Data will be shared via secure data transfer, following approval of a data-sharing agreement.

Drug and device information, study documents

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