The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling.

Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.

The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt- mTOR signaling.

Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ΔIg3-MuSKmice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.

Quantifying the Effects of Two Local Anesthetics on the Crayfish Stretch Receptor Organ: An Integrated Neurophysiology Lab.

The crayfish stretch receptor organ (SRO) preparation represents a robust experimental model for undergraduate laboratory experiences. For example, this preparation may be included as part of a course-based undergraduate research experience (CURE), where students work independently to plan and carry out their own experiments. In the current paper, we provide an example of how local anesthetics may be used to manipulate the SRO preparation and to perform quantitative analyses of SRO action potential firing rates. Local anesthetics provide interesting tools for manipulating physiological responses within the nervous system. A variety of inexpensive anesthetics are available for student use and each of these is expected to inhibit neurophysiological responses. While specific anesthetics exhibit subtle differences in chemical organization, they are generally understood to block voltage gated sodium channels. In the current study, we investigated the effects of two local anesthetics, MS-222 and procaine, on the action potential firing rate from the crayfish SRO. Using quantitative analyses of SRO action potential generation, we determined that each anesthetic has unique inhibitory effects on action potential firing rate that may be explained by their neuropharmacological properties. This manipulation may thus be utilized as an interesting experimental tool in undergraduate teaching laboratories. Local anesthetics applied to crayfish SRO preparations can thus be used to deepen student understanding of local anesthetics, exercise quantitative analyses, and provide experimental tools for independent experimental design.