Whereas most kinesins motor along microtubules, KinI kinesins are microtubule depolymerizing machines. Surprisingly, we found that a KinI fragment consisting of only the motor core is capable of ATP-dependent depolymerization. The motor binds along microtubules in all nucleotide states, but in the presence of AMPPNP, microtubule depolymerization also occurs. Structural characterization of the products of AMPPNP-induced destabilization revealed a snapshot of the disassembly machine in action as it precisely deformed a tubulin dimer. While conventional kinesins use the energy of ATP binding to execute a "powerstroke," KinIs use it to bend the underlying protofilament. Thus, the relatively small class-specific differences within the KinI motor core modulate a fundamentally conserved mode of interaction with microtubules to produce a unique depolymerizing activity.

Members of the kinesin-8 motor class have the remarkable ability to both walk towards microtubule plus-ends and depolymerise these ends on arrival, thereby regulating microtubule length. To analyse how kinesin-8 multitasks, we studied the structure and function of the kinesin-8 motor domain. We determined the first crystal structure of a kinesin-8 and used cryo-electron microscopy to calculate the structure of the microtubule-bound motor. Microtubule-bound kinesin-8 reveals a new conformation compared with the crystal structure, including a bent conformation of the α4 relay helix and ordering of functionally important loops. The kinesin-8 motor domain does not depolymerise stabilised microtubules with ATP but does form tubulin rings in the presence of a non-hydrolysable ATP analogue. This shows that, by collaborating, kinesin-8 motor domain molecules can release tubulin from microtubules, and that they have a similar mechanical effect on microtubule ends as kinesin-13, which enables depolymerisation. Our data reveal aspects of the molecular mechanism of kinesin-8 motors that contribute to their unique dual motile and depolymerising functions, which are adapted to control microtubule length.

During embryonic development, IGF-1 fulfils crucial roles in skeletal myogenesis. However, the involvement of IGF-1-induced myoblast proliferation in muscle growth is still unclear. In the present study, we have characterised the role of IGF-1 in myoblast proliferation both in vitro and in vivo and have revealed novel details of how exogenous IGF-1 influences myogenic genes in chicken embryos. The results show that IGF-1 significantly induces the proliferation of cultured myoblasts in a dose-dependent manner. Additionally, the IGF-1 treatment significantly promoted myoblasts entering a new cell cycle and increasing the mRNA expression levels of cell cycle-dependent genes. However, these effects were inhibited by the PI3K inhibitor LY294002 and the Akt inhibitor KP372-1. These data indicated that the pro-proliferative effect of IGF-1 was mediated in response to the PI3K/Akt signalling pathway. Moreover, we also showed that exogenous IGF-1 stimulated myoblast proliferation in vivo. IGF-1 administration obviously promoted the incorporation of BrdU and remarkably increased the number of PAX7-positive cells in the skeletal muscle of chicken embryos. Administration of IGF-1 also significantly induced the upregulation of myogenic factors gene, the enhancement of c-Myc and the inhibition of myostatin (Mstn) expression. These findings demonstrate that IGF-1 has strong activity as a promoter of myoblast expansion and muscle fiber formation during early myogenesis. Therefore, this study offers insight into the mechanisms responsible for IGF-1-mediated stimulation of embryonic skeletal muscle development, which could have important implications for the improvement of chicken meat production.

This study was conducted to evaluate the effect of curcumin on laying performance, egg quality, biochemical indicators, hormone levels, and immune activity in hens under heat stress. Hy-Line brown hens (280-day-old) were fed with 0, 100, 150, and 200 mg/kg of curcumin during a 42-D experiment. Compared with the control treatment, supplementation with 150 mg/kg of curcumin improved laying performance and egg quality by significantly increasing egg production, eggshell thickness, eggshell strength ( P < 0.01), and albumen height ( P < 0.05) while decreasing the feed-to-egg ratio. Antioxidant activity was improved by significantly increasing the activity of superoxide dismutase and glutathione peroxidase but decreasing malondialdehyde levels in serum ( P < 0.05) and significantly increasing the levels of follicle-stimulating hormone, luteinizing hormone, estradiol, IgG, IgA, and complement C 3 activity in serum ( P < 0.05). These results indicated that supplemental 150 mg/kg curcumin can improve productive performance, antioxidant enzyme activity, and immune function in laying hens under the heat stress conditions applied in the present study.

A hallmark feature of myosin-II is that it can spontaneously self-assemble into bipolar synthetic thick filaments (STFs) in low ionic strength buffers, thereby serving as a reconstituted in-vitro model for muscle thick filament. While these STFs have been extensively used for structural characterization, their functional evaluation has been limited.  In this report, we show that myosins in STFs mirror the more electrostatic and cooperative interactions that underlie the energy-sparing super-relaxed (SRX) state, which are not seen using shorter myosin sub-fragments, heavy meromyosin (HMM) and myosin subfragment-1 (S1). Using these STFs, we show several pathophysiological insults in hypertrophic cardiomyopathy, including the R403Q myosin mutation, phosphorylation of myosin light chains, and increased ADP:ATP ratio destabilize the SRX population. Furthermore, wild-type myosin containing STFs, but not S1, HMM, or STFs-containing R403Q myosin, recapitulated the ADP-induced destabilization of the SRX state. Studies involving a clinical-stage small molecule inhibitor, mavacamten, showed that it is not only more effective in increasing myosin SRX population in STFs than in S1 or HMM ,  but it also increases myosin SRX population equally well in STFs made of healthy and disease-causing R403Q myosin. Importantly, we also found that pathophysiological perturbations   such as elevated ADP concentration weakens the mavacamten’s ability to increase the myosin SRX population, suggesting that mavacamten-bound myosin heads are not permanently protected in the SRX state but can be recruited   into action. These findings collectively emphasize that STFs serve as a valuable tool to provide novel insights into the myosin SRX state in healthy, disease, and therapeutic conditions.