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Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by autophagy from death with autophagy, and whether autophagy contributes to death in cardiomyocytes (CMs) is still controversial. Excessive activation of autophagy induces a morphologically and biochemically defined form of cell death termed autosis. Whether autosis is involved in tissue injury induced under pathologically relevant conditions is poorly understood. In the present study, myocardial ischemia/reperfusion (I/R) induced autosis in CMs, as evidenced by cell death with numerous vacuoles and perinuclear spaces, and depleted intracellular membranes. Autosis was observed frequently after 6 hours of reperfusion, accompanied by upregulation of Rubicon, attenuation of autophagic flux, and marked accumulation of autophagosomes. Genetic downregulation of Rubicon inhibited autosis and reduced I/R injury, whereas stimulation of autosis during the late phase of I/R with Tat-Beclin 1 exacerbated injury. Suppression of autosis by ouabain, a cardiac glycoside, in humanized Na+,K+-ATPase-knockin mice reduced I/R injury. Taken together, these results demonstrate that autosis is significantly involved in I/R injury in the heart and triggered by dysregulated accumulation of autophagosomes due to upregulation of Rubicon.

Glioblastoma multiforme (GBM) is a fatal malignancy of the central nervous system, commonly associated with chemoresistance. The alkylating agent Temozolomide (TMZ) is the front-line chemotherapeutic agent and has undergone intense studies on resistance. These studies reported on mismatch repair gene upregulation, ABC-targeted drug efflux, and cell cycle alterations. The mechanism by which TMZ induces cell cycle arrest has not been well-established. TMZ-resistant GBM cells have been linked to microRNA (miRNA) and exosomes. A cell cycle miRNA array identified distinct miRNAs only in exosomes from TMZ-resistant GBM cell lines and primary spheres. We narrowed the miRs to miR-93 and -193 and showed in computational analyses that they could target Cyclin D1. Since Cyclin D1 is a major regulator of cell cycle progression, we performed cause-effect studies and showed a blunting effects of miR-93 and -193 in Cyclin D1 expression. These two miRs also decreased cell cycling quiescence and induced resistance to TMZ. Taken together, our data provide a mechanism by which GBM cells can exhibit TMZ-induced resistance through miRNA targeting of Cyclin D1. The data provide a number of therapeutic approaches to reverse chemoresistance at the miRNA, exosomal and cell cycle points.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD cardiomyopathy is characterized by abnormal intracellular Ca2+ homeostasis and mitochondrial dysfunction. We used dystrophin and utrophin double-knockout (mdx:utrn-/-) mice in a sarcolipin (SLN) heterozygous-knockout (sln+/-) background to examine the effect of SLN reduction on mitochondrial function in the dystrophic myocardium. Germline reduction of SLN expression in mdx:utrn-/- mice improved cardiac sarco/endoplasmic reticulum (SR) Ca2+ cycling, reduced cardiac fibrosis, and improved cardiac function. At the cellular level, reducing SLN expression prevented mitochondrial Ca2+ overload, reduced mitochondrial membrane potential loss, and improved mitochondrial function. Transmission electron microscopy of myocardial tissues and proteomic analysis of mitochondria-associated membranes showed that reducing SLN expression improved mitochondrial structure and SR-mitochondria interactions in dystrophic cardiomyocytes. These findings indicate that SLN upregulation plays a substantial role in the pathogenesis of cardiomyopathy and that reducing SLN expression has clinical implications in the treatment of DMD cardiomyopathy.

The process of human cardiac development can be faithfully recapitulated in a culture dish with human pluripotent stem cells, where the impact of environmental stressors can be evaluated. The consequences of ionizing radiation exposure on human cardiac differentiation are largely unknown. In this study, human‐induced pluripotent stem cell cultures (hiPSCs) were subjected to an external beam of 3.7 MeV α‐particles at low mean absorbed doses of 0.5, 3, and 10 cGy. Subsequently, the hiPSCs were differentiated into beating cardiac myocytes (hiPSC‐CMs). Pluripotent and cardiac markers and morphology did not reveal differences between the irradiated and nonirradiated groups. While cell number was not affected during CM differentiation, cell number of differentiated CMs was severely reduced by ionizing radiation in a dose‐responsive manner. β‐adrenergic stimulation causes calcium (Ca2+) overload and oxidative stress. Although no significant increase in Ca2+ transient amplitude was observed in any group after treatment with 1 μmol/L isoproterenol, the incidence of spontaneous Ca2+ waves/releases was more frequent in hiPSC‐CMs of the irradiated groups, indicating arrhythmogenic activities at the single cell level. Increased transcript expression of mitochondrial biomarkers (LONP1, TFAM) and mtDNA‐encoded genes (MT‐CYB, MT‐RNR1) was detected upon differentiation of hiPSC‐CMs suggesting increased organelle biogenesis. Exposure of hiPSC‐CM cultures to 10 cGy significantly upregulated MT‐CYB and MT‐RNR1 expression, which may reflect an adaptive response to ionizing radiation. Our results indicate that important aspects of differentiation of hiPSCs into cardiac myocytes may be affected by low fluences of densely ionizing radiations such as α‐particles. Human‐induced pluripotent stem cells (hiPSCs) maintained in culture are exposed to low fluences of α‐particles. Irradiated hiPSCs were then differentiated into beating cardiomyocytes (hiPSC‐CMs), and molecular, morphological, and functional assessments were conducted. We report that low mean absorbed doses of α‐particles applied to hiPSCs does not affect their capacity to become beating cardiomyocytes, but has direct consequences on spontaneous Ca2+ beating and number of the differentiated cardiomyocytes obtained.

Sympathetic nerves co-develop with their target organs and release neurotransmitters to stimulate their functions after maturation. Here, we provide the molecular mechanism that during sweat gland morphogenesis, neurotransmitters released from sympathetic nerves act first to promote sweat duct elongation via norepinephrine and followed by acetylcholine to specify sweat gland stem cell fate, which matches the sequence of neurotransmitter switch. Without neuronal signals during development, the basal cells switch to exhibit suprabasal (luminal) cell features. Sarcolipin (SLN), a key regulator of sarcoendoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA), expression is significantly down-regulated in the sweat gland myoepithelial cells upon denervation. Loss of SLN in sweat gland myoepithelial cells leads to decreased intracellular Ca 2+ over time in response to ACh stimulation, as well as upregulation of luminal cell features. In cell culture experiments, we showed that contrary to the paradigm that elevation of Ca 2+ promote epidermal differentiation, specification of the glandular myoepithelial (basal) cells requires high Ca 2+ while lowering Ca 2+ level promotes luminal (suprabasal) cell fate. Our work highlights that neuronal signals not only act transiently for mature sweat glands to function, but also exert long-term impact on glandular stem cell specification through regulating intracellular Ca 2+ dynamics.Sympathetic nerves co-develop with their target organs and release neurotransmitters to stimulate their functions after maturation. Here, we provide the molecular mechanism that during sweat gland morphogenesis, neurotransmitters released from sympathetic nerves act first to promote sweat duct elongation via norepinephrine and followed by acetylcholine to specify sweat gland stem cell fate, which matches the sequence of neurotransmitter switch. Without neuronal signals during development, the basal cells switch to exhibit suprabasal (luminal) cell features. Sarcolipin (SLN), a key regulator of sarcoendoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA), expression is significantly down-regulated in the sweat gland myoepithelial cells upon denervation. Loss of SLN in sweat gland myoepithelial cells leads to decreased intracellular Ca 2+ over time in response to ACh stimulation, as well as upregulation of luminal cell features. In cell culture experiments, we showed that contrary to the paradigm that elevation of Ca 2+ promote epidermal differentiation, specification of the glandular myoepithelial (basal) cells requires high Ca 2+ while lowering Ca 2+ level promotes luminal (suprabasal) cell fate. Our work highlights that neuronal signals not only act transiently for mature sweat glands to function, but also exert long-term impact on glandular stem cell specification through regulating intracellular Ca 2+ dynamics.