Rates of diabetes-related complications have declined substantially in the past two decades, but a large burden of disease persists because of the continued increase in the prevalence of diabetes. (Funded by the Centers for Disease Control and Prevention.).

Analyses of nationally representative data from 1980 to 2012 suggest a doubling of the incidence and prevalence of diabetes during 1990-2008, and a plateauing between 2008 and 2012. However, there appear to be continued increases in the prevalence or incidence of diabetes among subgroups, including non-Hispanic black and Hispanic subpopulations and those with a high school education or less.

Mitochondrial preproteins destined for the matrix are translocated by two channel-forming transport machineries, the translocase of the outer membrane and the presequence translocase of the inner membrane. The presequence translocase-associated protein import motor (PAM) contains four essential subunits: the matrix heat shock protein 70 (mtHsp70) and its three cochaperones Mge1, Tim44 and Pam18. Here we report that the PAM contains a fifth essential subunit, Pam16 (encoded by Saccharomyces cerevisiae YJL104W), which is selectively required for preprotein translocation into the matrix, but not for protein insertion into the inner membrane. Pam16 interacts with Pam18 and is needed for the association of Pam18 with the presequence translocase and for formation of a mtHsp70-Tim44 complex. Thus, Pam16 is a newly identified type of motor subunit and is required to promote a functional PAM reaction cycle, thereby driving preprotein import into the matrix.

We previously demonstrated that multipotent mesenchymal stromal cells (MSCs) with overexpressed microRNA 133b (miR-133b) significantly improve functional recovery in rats subjected to middle cerebral artery occlusion (MCAO) compared with naive MSCs, and that exosomes generated from naive MSCs mediate the therapeutic benefits of MSC therapy for stroke. Here, we investigated whether exosomes isolated from miR-133b-overexpressed MSCs (Ex-miR-133b+) exert amplified therapeutic effects. Rats subjected to 2 hours (h) of MCAO were intra-arterially injected with Ex-miR-133b+, exosomes from MSCs infected by blank vector (Ex-Con), or phosphate-buffered solution (PBS), and were sacrificed 28 days post MCAO. Compared with the PBS treatment, both exosome treatment groups exhibited significant improvement of functional recovery. Ex-miR-133b+ treatment significantly increased functional improvement, and neurite remodeling/brain plasticity in the ischemic boundary area compared with the Ex-Con treatment. Treatment with Ex-miR-133b+ also significantly increased brain exosome content compared with Ex-Con treatment. To elucidate mechanisms underlying the enhanced therapeutic effects of Ex-miR-133b+, astrocytes cultured under oxygen and glucose deprived (OGD) conditions were incubated with exosomes harvested from naïve MSCs (Ex-Naive), miR-133b down-regulated MSCs (Ex-miR-133b−) and Ex-miR-133b+. Compared with the Ex-Naive treatment, Ex-miR-133b+ significantly increased exosomes released by OGD astrocytes, whereas Ex-miR-133b− significantly decreased the release. Also, exosomes harvested from OGD astrocytes treated with Ex-miR-133b+ significantly increased neurite branching and elongation of cultured cortical embryonic rat neurons compared with the exosomes from OGD astrocytes subjected to Ex-Con. Our data suggest that exosomes harvested from miR-133b-overexpressed MSCs improve neural plasticity and functional recovery after stroke with a contribution from a stimulated secondary release of neurite promoting exosomes from astrocytes.

Myostatin is a transforming growth factor ␤ superfamily member and is known as an inhibitor of skeletal muscle cell proliferation and differentiation. Exposure to myostatin induces G 1 phase cell cycle arrest. In this study, we demonstrated that myostatin down-regulates Cdk4 activity via promotion of cyclin D1 degradation. Overexpression of cyclin D1 significantly blocked myostatin-induced proliferation inhibition. We further showed that phosphorylation at threonine 286 by GSK-3␤ was required for myostatin-stimulated cyclin D1 nuclear export and degradation. This process is dependent upon the activin receptor IIB and the phosphatidylinositol 3-kinase/ Akt pathway but not Smad3. Insulin-like growth factor 1 (IGF-1) treatment or Akt activation attenuated the myostatin-stimulated cyclin D1 degradation as well as the associated cell proliferation repression. In contrast, attenuation of IGF-1 signaling caused C2C12 cells to undergo apoptosis in response to myostatin treatment. The observation that IGF-1 treatment increases myostatin expression through a phosphatidylinositol 3-kinase pathway suggests a possible feedback regulation between IGF-1 and myostatin. These findings uncover a novel role for myostatin in the regulation of cell growth and cell death in concert with IGF-1.