Tetrandrine Inhibits Skeletal Muscle Differentiation by Blocking Autophagic Flux

Abstract

Tetrandrine is well known to act as a calcium channel blocker. It is a potential candidate for a tumor chemotherapy drug without toxicity. Tetrandrine inhibits cancer cell proliferation and induces cell death through apoptosis and autophagy. As cancer patients usually experience complications with sarcopenia or muscle injury, we thus assessed the effects of tetrandrine on skeletal muscle cells. We report in this study that a low dose of tetrandrine (less than 5 μM) does not affect the proliferation of C2C12 myoblasts, but significantly inhibits myogenic differentiation. Consistently, tetrandrine inhibited muscle regeneration after BaCl2-induced injury. Mechanistic experiments showed that tetrandrine decreased the p-mTOR level and increased the levels of LC3 and SQSTM1/p62 during differentiation. Ad-mRFP-GFP-LC3B transfection experiments revealed that the lysosomal quenching of GFP signals was suppressed by tetrandrine. Furthermore, the levels of DNM1L/Drp1, PPARGA1 and cytochrome C (Cyto C), as well as caspase 3 activation and ROS production, were decreased following tetrandrine administration, indicating that the mitochondrial network signaling was inhibited. Our results indicate that tetrandrine has dual effects on autophagic flux in myoblasts during differentiation, activation in the early stage and blockade in the late stage. The ultimate blocking of autophagic flux by tetrandrine led to the disruption of mitochondria remodeling and inhibition of myogenic differentiation. The inhibitory effects of tetrandrine on skeletal muscle differentiation may limit its application in advanced cancer patients. Thus, great attention should be paid to the clinical use of tetrandrine for cancer therapy.

RNA-Sequencing Reveals Upregulation and a Beneficial Role of Autophagy in Myoblast Differentiation and Fusion

“…A positive role for autophagy in myoblast differentiation is supported by our results showing that blocking autophagy in C2C12 myoblasts impaired their expression of muscle-specific genes and their fusion into multinucleated myotubes. Our finding that autophagy plays a positive role in myoblast differentiation was consistent with earlier studies using different approaches or different myoblast models [ 24 , 25 , 26 , 27 , 28 , 29 ]. However, the conclusion that autophagy aids myoblast differentiation seems to contradict the observation that inducing autophagy with the mTOR inhibitor rapamycin inhibited myoblast differentiation in C2C12 cells [ 59 ].…”

“…This process includes packaging the target objects in the phagophores derived from the endoplasmic reticulum [ 20 ]; the expansion and sealing of the phagophores with various proteins, including different Atg isoforms [ 21 ]; the establishment of autophagosomes; and the fusion of autophagosomes with lysosomes to form autolysosomes, where the target material for recycling is degraded by lysosomal hydrolases. Autophagy has been linked to muscle regeneration following injury [ 12 ], muscle aging [ 22 ], muscle atrophy [ 23 ], and myoblast differentiation [ 24 , 25 , 26 , 27 , 28 , 29 ].…”

Research Progress on Neuroprotective Effects of Isoquinoline Alkaloids

“…The main neuroprotective mechanism involves regulating Ca 2+ and K + channels, maintaining intracellular calcium homeostasis, and reducing neuronal and glial cell damage caused by Ca 2+ overload [ 23 ]. In addition, it can regulate central neurotransmitter transport and metabolism, inhibit neuroinflammation, improve vascular endothelial dysfunction, decrease oxidative stress, and regulate autophagy [ 24 , 25 , 26 ]. It has a highly comprehensive neuroprotective effect and is a potential neuroprotective agent.…”

circUSP13 facilitates the fast‐to‐slow myofiber shift via the MAPK/ERK signaling pathway in goat skeletal muscles

“…In agreement with previous studies, Bryant et al observed that MAPK/ERK inhibition can block mitochondrial fission, leading to increased mitochondrial fusion (Bryant et al, 2019). Mitochondrial remodeling is critical for skeletal muscle differentiation and myofiber type transformation (Li et al, 2022). Thus, the cascade phosphorylation process MAPK/ERK plays a critical role in regulating myofiber conversion.…”