Exercise and muscle biology in systemic lupus erythematosus

Systemic lupus erythematosus is a long-term autoimmune disease that affects nearly six million people worldwide. Many people with lupus experience pain, but the symptom they most often describe as the hardest to live with is fatigue. This fatigue is constant and can make everyday activities—such as working, bathing, caring for family, or moving—very difficult or even impossible, even when the disease seems otherwise well controlled. At present, there are no medications that effectively treat fatigue in lupus.

One reason for fatigue may be problems with how muscles produce energy. Inside every cell are structures called mitochondria, which act like tiny power plants that provide energy for the body. Mitochondria are especially important in muscles. In people with lupus, mitochondria do not function as well as they should, which can lead to low energy levels and increased inflammation. In addition, people with lupus tend to have higher amounts of fat stored within their muscles. These fat deposits can release inflammatory signals, which may further damage muscle cells and worsen fatigue.

Certain types of exercise, especially high-intensity intermittent exercise, have been shown to improve muscle health in other chronic diseases by improving how mitochondria work and reducing fat within muscles. However, this type of exercise has not been well studied in people with lupus. We believe that a personalized exercise program, adjusted to each person’s fitness level, can safely improve mitochondrial function, reduce muscle fat, and decrease inflammation in people with lupus.

In this study, participants will complete a personalized, home-based high-intensity intermittent exercise program three times per week for 16 weeks. Each session will last about 40 minutes and will be supervised by video to ensure safety and support participation. Before and after the program, we will measure muscle health and muscle fat with images, blood markers, and patient-reported symptoms.

The goal of this research is to understand whether a personalized high-intensity intermittent exercise program can improve physical function in people with lupus through its effects on mitochondria and muscle fat depots. The results of our study will identify mechanisms affecting muscle health that can inform better interventions to improve quality of life for individuals living with lupus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that affects nearly six million people worldwide. Although musculoskeletal pain is common, fatigue is consistently identified by patients as the most burdensome symptom, affecting approximately 55–80% of individuals with SLE, including those with clinically stable disease. Fatigue is persistent and severely limits daily functioning. Because SLE-related fatigue is multifactorial, effective pharmacologic treatments are lacking.

Rationale: Emerging evidence implicates mitochondrial dysfunction as a key contributor to fatigue. Mitochondria are central regulators of cellular energy metabolism and play critical roles in innate immune signaling and inflammation through inflammasome activation and the release of immunogenic mitochondrial-derived molecules that amplify inflammatory pathways, including type I interferon responses. In conditions such as chronic kidney disease, mitochondrial dysfunction is associated with fatigue and exercise intolerance. Patients with SLE exhibit mitochondrial dysfunction and increased fat deposition within skeletal muscle, termed intermuscular adipose tissue (IMAT). IMAT is elevated in metabolic disease and aging and represents a distinct, highly inflammatory adipose depot that likely exacerbates muscle inflammation and further impairs mitochondrial function.

High-intensity exercise has been shown to improve muscle health by enhancing mitochondrial function and reducing muscle fat depots (including IMAT) in several chronic conditions, such as cardiovascular disease; however, the impact of high-intensity exercise has not been well studied in SLE.

Objective: The overall objective of this study is to determine the clinical and mechanistic impact of a 16-week, personalized, home-based high-intensity intermittent training (HB-HIIT) program on muscle health in patients with SLE.

Specific Aims

Aim 1: Test the hypothesis that a 16-week personalized HB-HIIT program improves skeletal muscle mitochondrial function in patients with SLE.

Aim 1a: Assess in vivo mitochondrial function using 31-phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive state-of-the-art technique for assessing mitochondrial function in muscle cells in humans, before and after exercise training.

Aim 1b: Evaluate physical performance before and after exercise training.

Aim 1c: Measure changes in circulating biomarkers of mitochondrial dysfunction (GDF-15, MOTS-c, humanin, BDNF, irisin, gelsolin, FGF-21, and cell-free mitochondrial DNA [cfmtDNA]) before and after exercise training.

Aim 2: Test the hypothesis that a 16-week personalized exercise program reduces intermuscular adipose tissue (IMAT) accumulation and systemic inflammation in patients with SLE.

Aim 2a: Quantify IMAT in the thigh muscle compartment using magnetic resonance imaging (MRI) before and after exercise training.

Aim 2b: Evaluate changes in inflammatory biomarkers (IL-6, TNF-α, IFN-α, and IL-17) before and after exercise training.

Innovation and feasibility: The proposed 16-week HB-HIIT program is individualized, video-supervised, and home-based, maximizing feasibility, safety, tolerability, and adherence. In addition, as an established LuCIN center, we have the experience to achieve our enrollment target and the resources needed to execute the proposed clinical study.

Impact: This study will determine whether a personalized exercise intervention improves physical function in SLE through its effects on mitochondrial function and IMAT. The findings will provide mechanistic insights to inform future non-pharmacologic strategies aimed at reducing fatigue and improving quality of life in patients with SLE.