FAM210A dictates mitochondrial OXPHOS efficiency to promote muscle function in peripheral artery disease

Introduction: Peripheral artery disease (PAD) is caused by occlusion of leg vessels, impairing walking ability. Evidence shows that restoring blood flow alone results in sub-optimal leg function recovery. As disease severity increases, patients exhibit impaired mitochondrial oxidative phosphorylation (OXPHOS) despite unchanged mitochondrial abundance. These findings indicate that both sufficient perfusion and mitochondrial OXPHOS are required to promote limb function in PAD, underscoring the need to target mitochondrial bioenergetics. FAM210A, a mitochondrial protein and emerging regulator of mitochondrial bioenergetics, is reduced in the calf muscle in severe PAD patients. We thus hypothesized that FAM210A is required to mitigate mitochondrial and skeletal muscle dysfunction during ischemia, and that restoring its expression would ameliorate these deficits. Methods: FAM210A-floxed C57BL/6J mice (N=35) and wild-type BALB/cJ mice (N=44) of both sexes were used. C57BL/6J mice show attenuated mitochondrial impairment and muscle function, and rapid restoration of FAM210A expression after ischemia, whereas BALB/cJ mice show severe mitochondrial dysfunction and muscle dysfunction, and delayed restoration of FAM210A expression. Hindlimb ischemia was induced by femoral artery ligation. Myofiber-specific deletion or restoration of FAM210A was achieved using AAVs with human skeletal actin (HSA) promoter and a MyoAAV serotype (MyoAAV4A-HSA-Cre or MyoAAV4A-HSA-FAM210A). At 21 days post-ischemia, muscle strength, mitochondrial OXPHOS conductance, and membrane potential were assessed. Limb function was measured using a 6-minute limb function test. Results: FAM210A expression is reduced in severe PAD patients at mRNA and protein levels (P=2.94E−10 and 0.0474). Myofiber-specific FAM210A loss in C57BL/6J mice after hindlimb ischemia impaired OXPHOS efficiency, reflected by a ~24.1% decrease in OXPHOS conductance (P=0.0034), accompanied by reduced mitochondrial membrane potential (P=1.76E−12 males; 6.11E−11 females). These led to impaired muscle strength (P=6.49E−8 males; 3.86E−21 females) and total work performed during the 6-minute limb function test (12477±4403 vs. 7911±2925 Joules, P=0.0045). Additionally, FAM210A-deficient mice had decreased muscle perfusion during the 6-minute limb function test (P=7.29E−7 males; P=2.23E−68 females), indicating reduced hyperemia. Conversely, restoring FAM210A in the skeletal muscle of BALB/cJ mice improved OXPHOS efficiency by ~59.2% (P=0.0074), and enhanced mitochondrial membrane potential (P=0.0006 males; 0.033 females). Restoring FAM210A expression also resulted in greater muscle strength (P=1.07E−6 males; P=0.002 females) and total work performed during the 6-minute limb function test compared to controls (5107±682 vs. 3139±873 Joules, P=0.0171). Muscle perfusion during the 6-minute limb function test was significantly higher in mice with MyoAAV4A-HSA-FAM210A treatment (P=1.09E−90 males; P=1.41E−27 females). Conclusion: This study establishes FAM210A as a central regulator of mitochondrial OXPHOS function in ischemic muscle. A deficiency in FAM210A was found to reduce OXPHOS efficiency leading to compromised muscle strength and work output. Therapeutic rescue of FAM210A expression significantly improved mitochondrial OXPHOS leading to greater muscle strength and work output in mice with hindlimb ischemia. Together, these findings position FAM210A as a potential bioenergetic target for therapeutic intervention in PAD. Funding Information: This work was supported by NIH R01-HL149704, R01-AR080687 (T.E.R.), R01-DK136722 (F.Y.) and AHA 25EIAI369187 (T.E.R.), 24PRE1191760 (G.D.). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.