The Importance of mTORC1-Autophagy Axis for Skeletal Muscle Diseases

Abstract

The mechanistic target of rapamycin (mTOR) complex 1, mTORC1, integrates nutrient and growth factor signals with cellular responses and plays critical roles in regulating cell growth, proliferation, and lifespan. mTORC1 signaling has been reported as a central regulator of autophagy by modulating almost all aspects of the autophagic process, including initiation, expansion, and termination. An increasing number of studies suggest that mTORC1 and autophagy are critical for the physiological function of skeletal muscle and are involved in diverse muscle diseases. Here, we review recent insights into the essential roles of mTORC1 and autophagy in skeletal muscles and their implications in human muscle diseases. Multiple inhibitors targeting mTORC1 or autophagy have already been clinically approved, while others are under development. These chemical modulators that target the mTORC1/autophagy pathways represent promising potentials to cure muscle diseases.

FOXO-regulated Deaf1 controls muscle regeneration through autophagy

“…However, hyperactive autophagy has been shown to reduce the proliferative capacity of MuSCs, which plays an important role in the early regeneration of damaged skeletal muscle in myotonic dystrophy type 1 (DM1) [34]. Therefore, these findings suggest that both deficient and excessive autophagy in MuSCs result in a pathological cascade and lead to muscle atrophy symptoms [3, 35].…”

“…MuSCs dysfunction has been linked to multiple human muscle diseases, including sarcopenia and cancer cachexia [3]. We thus tested the roles of Deaf1 in these diseases by examining Deaf1 expression levels.…”

“…Skeletal muscle accounts for approximately 40–50% of total body weight and plays key roles in movement, thermogenesis, and maintenance of energy homeostasis [1]. With the constant need for adaptability and the ability to acclimatize to physical demands such as growth and hypertrophy training, it is vital that skeletal muscles are able to regenerate from injury or regular wear and tear [2, 3]. This regenerative ability is primarily dependent on a population of MuSCs, also known as satellite cells, which are located underneath the basal lamina of the myofiber [3].…”

“…With the constant need for adaptability and the ability to acclimatize to physical demands such as growth and hypertrophy training, it is vital that skeletal muscles are able to regenerate from injury or regular wear and tear [2, 3]. This regenerative ability is primarily dependent on a population of MuSCs, also known as satellite cells, which are located underneath the basal lamina of the myofiber [3]. Under resting conditions, MuSCs are generally characterized by the expression of the myogenic transcription factor, paired box 7 (Pax7) and are maintained in a quiescent state [4].…”

Determining the Mechanism of Banxia Xiexin Decoction for Gastric Cancer Treatment through Network Analysis and Experimental Validation

“…The mTORC1 complex, which is a component of this pathway, inhibits autophagosome generation by phosphorylating autophagy regulatory complex ULK1. Under starvation conditions, mTORC1 inactivation causes ULK1 complex activation and promotes autophagosome nucleation via PI3KC3-CI activation. , AKT activation suppresses cell apoptosis by inhibiting Caspase-9, phosphorylating Bcl-2, and disrupting its association with the mitochondrial membrane . Persistent PI3K/Akt/mTOR pathway activation is significant in sustaining malignant tumors.…”