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.
Inclusion criteria for young controls
Healthy young adults (18-35 years old)
Without any pathology or treatment
Inclusion criteria for older controls
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
Parallel
Short-duration resistance training
Other interventionThe 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).
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).
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.
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).
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).
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.
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Fundación para la Investigación del Hospital Clínico de Valencia
Lead sponsor
University of Valencia
Collaborator
Ministerio de Ciencia e Innovación, Spain
Collaborator
