Involvement of Muscle Mitochondrial Dysfunction in Frailty in Older Adults. Role of Exercise
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Change in Mitochondrial Oxidative Phosphorylation (OXPHOS) Capacity in Skeletal Muscle
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Investigator)
入排标准
- 年龄范围
- 18 Years 至 83 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Group of healthy trained old people
Elderly patient without diagnosis of type 2 diabetes mellitus
干预措施: Short-duration resistance training (Other)
Group of type 2 diabetic trained old patients
Elderly patient diagnosed with type 2 diabetes mellitus
干预措施: Short-duration resistance training (Other)
Group of healthy trained young people
Young healthy control subjects
干预措施: Short-duration resistance training (Other)
结局指标
主要结局
Change in Mitochondrial Oxidative Phosphorylation (OXPHOS) Capacity in Skeletal Muscle
时间窗: Baseline and after 6 weeks of supervised resistance training
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)
时间窗: Baseline and after 6 weeks of supervised resistance training
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).
次要结局
- Change in Mitochondrial Quality Control Protein Expression in Skeletal Muscle(Baseline and after 6 weeks of supervised resistance training)
- Change in Whole-Body Lean Mass(Baseline and after 6 weeks of supervised resistance training)
- Change in Whole-Body Fat Mass(Baseline and after 6 weeks of supervised resistance training)
- Change in 6-Minute Walk Test Distance(Baseline and after 6 weeks of supervised resistance training)
- Change in Blood Glucose-6-Phosphate Dehydrogenase (G6PD) Activity(Baseline and after 6 weeks of supervised resistance training)
- Change in Skeletal Muscle Cell-Type-Specific Transcriptomic Profiles(Baseline and after 6 weeks of supervised resistance training)
- Change in Gut Microbiota Alpha Diversity(Baseline and after 6 weeks of supervised resistance training)
- Change in Quadriceps Muscle Thickness(Baseline and after 6 weeks of supervised resistance training)
- Change in Skeletal Muscle Fibre Cross-Sectional Area(Baseline and after 6 weeks of supervised resistance training)
- Change in Short Physical Performance Battery (SPPB) Score(Baseline and after 6 weeks of supervised resistance training)
- Change in FallSkip Test Performance Time(Baseline and after 6 weeks of supervised resistance training)
- Change in Blood Malondialdehyde (MDA) Levels(Baseline and after 6 weeks of supervised resistance training)
- Change in Fried Frailty Phenotype Score(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)(Baseline and after 6 weeks of supervised resistance training)
- Change in Quadriceps Extension 3-Repetition Maximum (3RM)(Baseline and after 6 weeks of supervised resistance training)
- Change in Skeletal Muscle Chromatin Accessibility Profiles Assessed by ATAC-seq(Baseline and after 6 weeks of supervised resistance training)
- Change in Plasma Proteomic Profiles(Baseline and after 6 weeks of supervised resistance training)