An interventional study of Short-duration resistance training in Diabetes Type 2, Frail Elderly Syndrome and Mitochondrial Function, Bioenergetics, sponsored by Fundación para la Investigación del Hospital Clínico de Valencia. Recruiting at 1 site in Spain. Open to participants aged 18 Years to 83 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-09-18.
Sponsored by Fundación para la Investigación del Hospital Clínico de Valencia · Not applicable, Interventional, and Treatment
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.
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:
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:
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.
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:
Muscle Biopsy Analyses
Muscle tissue samples will be used to examine:
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:
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:
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.
10,371 studies on the registry are indexed under Diabetes Mellitus, Type 2; 1,406 are open to participants now.
This study's planned enrollment of 120 is above the median of 80 across 8,350 interventional studies indexed under Diabetes Mellitus, Type 2.
Browse Diabetes Mellitus, Type 2 studies →Fundación para la Investigación del Hospital Clínico de Valencia is the lead sponsor of 73 studies on the registry; 18 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria:
Inclusion criteria for young controls
Inclusion criteria for older controls
Inclusion criteria for cases
Exclusion Criteria:
Exclusion criteria for young controls
Exclusion criteria for older controls
Exclusion criteria for cases
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
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HbA1c
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
COPD
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Elderly patient without diagnosis of type 2 diabetes mellitus
Other: Short-duration resistance training
Elderly patient diagnosed with type 2 diabetes mellitus
Other: Short-duration resistance training
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.
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).
Time frame: 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).
Time frame: Baseline and after 6 weeks of supervised resistance training
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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and after 6 weeks of supervised resistance training
Plan to share: Yes — 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.
Time frame: Beginning 12 months after publication of the primary results and for a period of 5 years thereafter.
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.
Started Jan 2022 (actual). Primary completion is estimated for Jul 2028, 78 months after the start.
Of 2,066 non-industry interventional studies with no phase under Diabetes Mellitus, Type 2, half reached primary completion within 21 months of starting (the median), counting those still running; a quarter within 10 and three quarters within 40. This study's planned 78 months is above that.
Counting every sponsor, half of 2,243 studies reached it within 21 months; a quarter within 10 and three quarters within 39.
How these figures are worked out, and which studies are left out of them.
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Fundación para la Investigación del Hospital Clínico de Valencia