Simmaron Research Inc

ATG13: A NEW PLAYER IN ME/CFS - PROJECT SUMMARY: MYALGIC ENCEPHALOMYELITIS AND CHRONIC FATIGUE SYNDROME (ME/CFS) IS A MULTISYSTEM CHRONIC ILLNESS CHARACTERIZED BY EXTREME FATIGUE, MUSCLE WEAKNESS, MUSCLE PAIN, DIZZINESS, A COGNITIVE DEFICIT OF ATTENTION, AND DEPRESSION. DESPITE INTENSE INVESTIGATION, THE MOLECULAR MECHANISM OF THIS DISEASE IS STILL UNKNOWN. OUR RECENT FINDING SUGGESTS THAT THE FUNCTIONAL INACTIVATION OF ATG13, AN ESSENTIAL PROTEIN OF CELLULAR AUTOPHAGY, CONTRIBUTES TO THE PATHOGENESIS OF ME/CFS. TO FURTHER CHARACTERIZE THE ROLE OF ATG13 IN THE PATHOGENESIS OF ME/CFS, A RELIABLE DISEASE MODEL IS REQUIRED THAT EXHIBITS SOME OF THE CARDINAL DISEASE SYMPTOMS SUCH AS POST-EXERTIONAL MALAISE (PEM) AND ORTHOSTATIC INTOLERANCE (OI). PEM IS CHARACTERIZED BY SEVERE MUSCLE FATIGUE AND PAINS IMMEDIATELY AFTER EXERCISE, WHEREAS OI IS CHARACTERIZED BY THE SUDDEN DROP IN BLOOD PRESSURE IN AN UPRIGHT CONDITION. OUR PRELIMINARY RESULTS SUGGEST THAT MHY1485, AN AGONIST OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR), INACTIVATES ATG13-DEPENDENT AUTOPHAGY AND INDUCES SEVERE FATIGUE AND PEM IN 3-4 WEEKS OLD FEMALE MICE. THEREFORE, TO ESTABLISH THE DIRECT ROLE OF ATG13 IN ME/CFS PATHOGENESIS, OUR OVERALL HYPOTHESIS IS THAT ATG13 DEPLETION WILL DISPLAY A SPONTANEOUS PEM PATHOLOGY. IN AIM1, WE WILL GENERATE A MOUSE STRAIN WITH MUSCLE-SPECIFIC KNOCK-OUT OF THE ATG13 GENE (ATG13MUSCLE). A 20-MINUTE ACUTE TREADMILL RUNNING PROTOCOL AND 2-DAYS CPET TESTS WOULD BE ADOPTED IN THESE MICE FOLLOWED BY SIMULTANEOUS MEASUREMENT OF M- WAVE AMPLITUDE THROUGH EMG RECORDING, DECREASED MOBILITY RECORDED BY STOELTING ANY-MAZE TRACKING SOFTWARE, MUSCLE PAIN, STRESS, AND NEUROCOGNITIVE IMPAIRMENT OF ATTENTION (AIM 1.1). MOLECULAR ANALYSIS OF MITOCHONDRIAL IMPAIRMENT IN ENERGY METABOLISM, CALCIUM HOMEOSTASIS, APOPTOSIS, AND ANAEROBIC GLYCOLYSIS WOULD BE EVALUATED IN THESE MICE (AIM 1.2). UNDER AIM2, WE WOULD SEE IF NEURAL MUTATION OF ATG13 IN MYELINATING CELLS OF THE BRAIN (ATG13BRAIN) OR ABLATION OF ATG13 IN SENSORY NEURONS (ATG13PNS) CONTRIBUTES TO THE PATHOGENESIS OF ME/CFS SUCH AS AUTONOMIC DYSFUNCTION, THE COGNITIVE DEFICIT OF ATTENTION, ANXIETY, AND PAIN. BRIEFLY, ATG13BRAIN AND ATG13PNS MICE WOULD BE GENERATED AND THEN ANALYZED FOR CHRONIC FATIGUE, FOLLOWED BY A 2-DAYS CPET TEST. AFTER ANOTHER 3-4 WEEKS, MUSCLE FATIGUE, PAIN, STRESS, AND NEUROCOGNITIVE IMPAIRMENT (AIM 2.1) WOULD BE EVALUATED. SINCE CHRONIC INFLAMMATION IS ONE OF THE CARDINAL SYMPTOMS OF ME/CFS, WE WOULD ASSESS PERIPHERAL INFLAMMATION OF CD4 TH1 CELL ACTIVATION IN THE SPLEEN- AND LYMPH NODE-DERIVED MONONUCLEAR CELLS (AIM 2.2). CENTRAL INFLAMMATION WILL BE ASSESSED BY MONITORING THE ACTIVATION OF NF-B, INOS, AND RANTES PRODUCTION IN THE BRAIN AND SPINAL CORD (AIM 2.2). IF SUCCESSFUL, OUR CURRENT PROPOSAL IDENTIFIES THE FIRST MOUSE MODEL TO STUDY ME/CFS AND ME/CFS- ASSOCIATED PEM.