Driving research of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS),
Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia and Post COVID .

Investigation into Post-Exertional Malaise
Between Historical and Recent ME/CFS

The study expands on a previously-awarded proposal to thoroughly explore the underlying pathophysiology of post exertional malaise (PEM), the hallmark symptom of ME/CFS.

  • David Systrom, MD, PhD
  • Wenzhong Xiao, PhD
  • Using a previously established 2-Day CPET protocol, the researchers will determine whether functional changes within the mitochondria were present by performing a biopsy of the vastus lateralis, one of four major muscles in the anterior thigh, as well as isolation of specialized immune cells from pre and post exercise blood draws. Dysfunction of the mitochondria have demonstrated decreased ability to use oxygen during exercise and possible interference in energy production.
  • The impact of PEM on ventilatory and pulmonary gas exchange measures will also be assessed. Specifically, we will look at changes in how the patients utilize oxygen, their achieved workload, and how efficiently they respired at peak exercise and at the ventilatory threshold, also known as the point at which the body becomes more dependent on acquiring energy from mechanisms not involving oxygen. With this data, the researchers will compare measures within and between groups to demonstrate the effect of PEM in ME/CFS patients due to exercise.
  • Additional novel approaches of this study include the isolation of extracellular vesicles (EVs) which can be isolated from blood after release from skeletal muscles, as well as exploring the role of red blood cell deformability in potentially inhibited oxygen delivery.

The hallmark symptom of ME/CFS is the flu-like worsening of symptoms after physical, mental, or emotional exertion known as post exertional malaise (PEM). The underlying mechanism behind this response is currently unknown, and this study aims to contribute useful insights to begin filling this gap. Twenty ME/CFS patients (10 recent and 10 historical) and 10 controls will complete 2-Day serial cardiopulmonary exercise tests (CPET) to not only stimulate physical exertion but also gather pulmonary gas exchange data in these groups. In addition, muscle biopsies after each CPET as well as pre and post blood draws will be performed to provide further mechanistic insights into PEM.


1. Assess the relevance of mitochondrial dysfunction after acute exercise to post exertional malaise.

  • Assess mitochondrial electron transport chain function and citrate synthase activity in limb skeletal muscle after exhaustive exercise on two consecutive days.
  • Assess mitochondrial electron transport chain function and citrate synthase activity in peripheral blood mononuclear cells (PBMCs) before and after exhaustive exercise.

2. Determine the prevalence of red blood cell deformability in ME/CFS.

  • Assess changes in peak exercise ventilation and pulmonary gas exchange measures using serial non-invasive cardiopulmonary exercise tests (CPET).
  • Characterize extracellular vesicles (EVs) isolated from ME/CFS patients and controls before and after two-day CPETs.
  • Assess the cytokine, transcriptomic, metabolomic and proteomic profiles in the blood and skeletal muscle in response to exercise.