Optimized Nutritional Interventions Improve Muscle Fatigue, Strength, and Quality of Life in Patients with Primary Mitochondrial Disease

Background Introduction

Primary mitochondrial disease (PMD) encompasses a group of disorders caused by mutations in mitochondrial DNA or nuclear DNA, affecting systemic energy metabolism. The prevalence is approximately 1 in 4,300 individuals, with clinical manifestations including muscle weakness, fatigue, exercise intolerance, gastrointestinal symptoms, and balance issues. Currently, there are no FDA-approved therapies specifically for PMD.

Mitochondria serve as the primary source of cellular energy by generating adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), a process influenced by the supply of macronutrients (carbohydrates, proteins, fats) and metabolic state. Although nutritional interventions have shown potential benefits, such as antioxidation or improved mitochondrial electron transport chain function, detailed studies on their effects and mechanisms in PMD remain scarce. Moreover, PMD-related complications, such as dysphagia, gastrointestinal dysmotility, and reduced appetite, exacerbate the risk of inadequate nutritional intake. Therefore, understanding the nutritional status of PMD patients and its impact on muscle function and quality of life is critical for optimizing clinical management strategies.

Research Overview

This study, conducted by the Mitochondrial Medicine Frontier Program at the Children’s Hospital of Philadelphia (CHOP), was published in the journal Neurotherapeutics in 2023. It is a prospective, single-center observational study designed to describe the nutritional intake status of genetically confirmed PMD patients, including adults (≥19 years, n=22) and children (<19 years, n=38), and to assess correlations between nutritional intake, muscle function, and quality of life.

Exclusively tube-fed patients were excluded from the study. Daily caloric requirements were estimated using the World Health Organization (WHO) equations combined with a newly developed Mitochondrial Disease Activity Factor (Motivator) to account for the unique activity limitations of PMD patients. Dietary intake data were collected through interviews and three-day food diaries.

Methods and Workflow

1. Study Design

The study included 60 genetically confirmed PMD patients: 22 adults and 38 children. Nutritional assessments included daily caloric needs, macronutrient intake (carbohydrates, proteins, fats), fluid consumption, and growth parameters (height, weight, BMI). Muscle function was objectively assessed using tools like handheld dynamometry and the 6-Minute Walk Test, and quality of life was evaluated using questionnaires such as PedsQL and Pedi-CAT.

2. Data Analysis

Correlations between nutritional intake and outcomes like muscle function and quality of life were analyzed using Pearson or Spearman correlations. Z-scores for children were calculated using Zanthro functions, and malnutrition was assessed based on AND/ASPEN and GLIM criteria.

Key Results

1. Prevalence of Inadequate Nutritional Intake

• Adults consumed an average of 1,143 ± 104.1 kcal/day, which was 76.2% of the predicted requirement; children consumed 1,114 ± 62.3 kcal/day, or 86.4% of the predicted requirement.
• A total of 29 (48.3%) patients consumed ≤75% of their predicted caloric needs, including 50% (n=¹¹⁄₂₂) of adults and 47.4% (n=¹⁸⁄₃₈) of children.

2. Macronutrient Intake Distribution

• Among adults, carbohydrates accounted for 42.1% of total caloric intake, proteins 14.5%, and fats 20.5%, all below recommended ranges.
• Among children, carbohydrates accounted for 44.1%, proteins 14.3%, and fats 29.0%, also failing to meet recommendations.

3. Correlation Between Nutritional Intake and Muscle Function

• Protein and fat intake were significantly negatively correlated with muscle fatigue (protein: r=-0.61, fat: r=-0.75), indicating reduced fatigue with increased intake.
• In patients with insufficient daily caloric intake, increased protein and fat intake improved strength in hip flexors and ankle dorsiflexors.
• Protein intake was positively correlated with quality of life (PedsQL scores), particularly physical and psychosocial functions.

4. Malnutrition Diagnosis

• Sixteen patients (26.7%) were diagnosed with malnutrition based on ASPEN criteria, including two adults and 14 children.
• Among children, 36.8% met malnutrition criteria, with 7 moderately malnourished and 6 severely malnourished.

5. Additional Findings

• Gastrointestinal symptoms (e.g., dysphagia [46.7%], constipation [43.3%]) were prevalent in 78.3% of patients, significantly affecting nutritional intake.
• Daily fluid intake was below recommendations, with adults consuming 76.1% and children consuming 77.3% of predicted values.

Conclusions and Significance

1. Study Conclusions

This study provides the first systematic analysis of daily caloric and macronutrient intake in genetically confirmed PMD patients, revealing widespread caloric deficiency, low fat intake, and malnutrition. Increased protein and fat intake significantly improved muscle function and quality of life.

2. Clinical Implications

• The study highlights the urgent need for individualized nutritional interventions in PMD, particularly increasing protein and fat intake.
• The development of the Motivator scoring system provides a scientific basis for determining personalized energy requirements in PMD patients.
• Future randomized controlled trials should validate the impact of optimized nutritional interventions on PMD outcomes.

3. Research Highlights

• Proposes a nutrition intervention model tailored to PMD patients’ specific needs.
• Establishes links between dietary intake and PMD symptoms (e.g., muscle fatigue).
• Offers new perspectives for nutritional management in mitochondrial diseases.

Summary

Optimized nutritional support holds significant potential in the treatment of PMD. This study provides valuable data and theoretical support for the development of precision nutritional interventions, paving the way for future clinical trials.