IGF-1 Signaling Regulates Mitochondrial Remodeling during Myogenic Differentiation

Abstract

Skeletal muscle is essential for locomotion, metabolism, and protein homeostasis in the body. Mitochondria have been considered as a key target to regulate metabolic switch during myo-genesis. The insulin-like growth factor 1 (IGF-1) signaling through the AKT/mammalian target of rapamycin (mTOR) pathway has a well-documented role in promoting muscle growth and regeneration, but whether it is involved in mitochondrial behavior and function remains un-examined. In this study, we investigated the effect of IGF-1 signaling on mitochondrial remodeling during myogenic differentiation. The results demonstrated that IGF-1 signaling stimulated mitochondrial biogenesis by increasing mitochondrial DNA copy number and expression of genes such as Cox7a1, Tfb1m, and Ppargc1a. Moreover, the level of mitophagy in differentiating myoblasts elevated significantly with IGF-1 treatment, which contributed to mitochondrial turnover. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) were identified as two key mediators of IGF-1-induced mitochondrial biogenesis and mitophagy, respectively. In addition, IGF-1 supplementation could alleviate impaired myoblast differentiation caused by mitophagy deficiency, as evidenced by increased fusion index and myosin heavy chain expression. These findings provide new insights into the role of IGF-1 signaling and suggest that IGF-1 signaling can serve as a target for the research and development of drugs and nutrients that support muscle growth and regeneration.

Self-Assembling Peptides with Insulin-Like Growth Factor Mimicry

“…This confirms the angiogenic potential of the peptide hydrogel in comparison to the IGF-1 condition . IGF-1 binding to its receptor initiates the PI3K/Akt pathway, which helps promote fusion as well as muscle development . To evaluate the myogenic potential of these peptides, C2C12 myoblast cells were incubated for 3–5 days (Figure S7).…”

“…40 IGF-1 binding to its receptor initiates the PI3K/Akt pathway, which helps promote fusion as well as muscle development. 41 To evaluate the myogenic potential of these peptides, C2C12 myoblast cells were incubated for 3−5 days (Figure S7). SLG 1 IGF, SLG 3 IGF, and SLG 5 IGF resulted in significant increases in multinucleated myotubes comparable to IGF-1 controls (Figure 4H).…”

Naringenin Promotes Myotube Formation and Maturation for Cultured Meat Production

“…IGF-1 is considered to be a factor closely related to skeletal muscle growth and hypertrophy. It can regulate protein synthesis and degradation, affect mitochondrial autophagy, and activate calcium signaling mediated by calcineurin [ 24 , 33 , 50 ]. By antagonizing ERβ with PHTPP, our study showed that, during the differentiation of PSCs in vitro, NAR mediated nuclear transfer of ERβ signaling to upregulate the expression of IGF-1 and promote the activation of IGF-1/Akt/mTOR anabolic pathway, thereby regulating myogenic differentiation and boosting myotube maturation.…”

“…After fixing with 4% paraformaldehyde (in PBS) at 25 °C for 15 min, cells were permeabilized with 0.5% Triton X-100 in PBS for 15 min and blocked with 1% BSA (in PBS) for 1 h. Then, cell samples were incubated with mouse anti-myosin heavy chain 3 (MYH3) antibody (Santa Cruz Biotechnology, CA, USA) or rabbit anti-Ki67 antibody (Cell Signaling Technology, Danvers, MA, USA) at 4 °C overnight and, subsequently, with CoraLite488-conjugated goat anti-mouse IgG (H + L) or CoraLite488-conjugated goat anti-rabbit IgG (H + L) (Proteintech Group, Wuhan, China) at 25 °C for 1 h. After staining with DAPI (Sigma-Aldrich, Burlington, MA, USA) for 10 min, samples were imaged with a fluorescence microscope (Mshot, Guangzhou, China). The fusion index was calculated as the percentage of nuclei in MYH3-positive myotubes (≥2 nuclei) to total nuclei within MYH3-positive myotubes [ 24 ]. At least 3 field images were analyzed per sample.…”

“…From the perspective of cultured meat production, medium modification is a simple and efficient way to improve production efficiency and product quality. Some growth factors, such as IGF-1 [ 24 ] and small molecular compounds such as dehydrocorydaline [ 25 ], silibinin [ 26 ], and resveratrol [ 27 ], have been reported to be beneficial for myogenic differentiation. However, most of the reported compounds only enhance embryonic MYH3 expression but fail to promote the maturation of myotubes or lack research data on more mature MYH subtypes.…”