The role of sknac in the mechanically induced growth of skeletal muscle

The National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded the University of Wisconsin System $164,000 on December 1, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846) to fund research into the role of the protein SKNAC in mechanically induced skeletal muscle growth.

The research investigates signaling pathways that promote muscle mass preservation and growth in response to mechanical loading. Preliminary data indicate that while radial fiber growth depends on mTORC1 signaling, longitudinal growth through in-series sarcomere addition proceeds through an mTORC1-independent pathway. A phosphoproteome-wide analysis identified SKNAC as a candidate regulator, with 30 distinct phosphorylation sites showing robust and sustained increases specifically following resistance exercise. Follow-up studies in a mouse resistance exercise model demonstrated that over 98 percent of SKNAC phosphorylation sites operate through mTORC1-independent mechanisms. The research aims to elucidate how mechanical signals regulate skeletal muscle mass and identify intervention targets to prevent physical decline.

Work is performed at the University of Wisconsin–Madison in Madison, Wisconsin. The period of performance runs from December 1, 2026, through May 31, 2029. This is a Project Grant, an assistance type providing support for investigator-initiated research.

Abstract

The preservation of skeletal muscle mass is critical for maintaining quality of life and resilience against various diseases; however, effective interventions to maintain or increase muscle mass and thereby prevent physical decline are limited. Simply put, there is a critical need to identify signaling pathways that can promote muscle growth. Previous studies have established that mechanical signals are one of the most potent inducers of muscle growth, yet the underlying mechanisms remain far from understood. As such, the long-term goal of my research is to determine how mechanical signals regulate skeletal muscle mass. A longstanding paradigm asserts that an increase in mechanical loading leads to an MTORC1-dependent accumulation of newly synthesized proteins (NSPS) which, in turn, can induce both the radial and longitudinal growth of muscle fibers. However, our preliminary data demonstrate that while the radial growth of fibers is prevented by MTORC1 inhibition, the in- series addition of sarcomeres (i.e., longitudinal growth) is not. In an effort to identify the components of this MTORC1-independent pathway, our lab performed a phosphoproteome-wide analysis of the signaling events that occur in human skeletal muscle after two types of exercise: endurance exercise, which results in elevated aerobic capacity, and resistance exercise, which increases protein synthesis and muscle mass. Among the outcomes, we found that a protein called sknac had 30 different sites that experienced a robust and sustained increase in phosphorylation specifically after resistance exercise. Follow-up studies in a mouse model of resistance exercise revealed that >98% of the sites phosphorylated on sknac were mediated through an MTORC1-independent pathway. This was very intriguing because previous studies have indicated that sknac can play a central role in the regulation of protein synthesis and sarcomerogenesis. Collectively, the aforementioned points led me to my central hypothesis: sknac is a key component of an MTORC1-independent pathway that regulates the mechanically induced growth of skeletal muscle. To test this hypothesis, I will leverage a combination of cutting-edge imaging techniques, two distinct models of mechanically induced growth (myotenectomy and weight pulling), and recently developed methods for analyzing kinase-substrate interactions. These technologies, along with my newly minted skeletal muscle-specific and inducible sknac knockout mouse, will enable me to test my hypothesis through the following aims: 1) determine whether sknac is necessary for the mechanically induced accumulation of NSPS at putative sites of growth; 2) determine whether sknac is necessary for the mechanically induced growth of skeletal muscle; 3) identify the kinase(S) that promote the mechanically induced phosphorylation of sknac. Collectively, the outcomes are expected to fill a major GAP in our understanding of how mechanical signals regulate skeletal muscle mass and when combined with my personalized training plan, they will enable me to acquire the skills necessary to achieve my goal of becoming a principal investigator at a research-intensive institution.