Interaction of Fibromodulin and Myostatin to Regulate Skeletal Muscle Aging: An Opposite Regulation in Muscle Aging, Diabetes, and Intracellular Lipid Accumulation

Abstract

The objective of this study was to investigate fibromodulin (FMOD) and myostatin (MSTN) gene expressions during skeletal muscle aging and to understand their involvements in this process. The expressions of genes related to muscle aging (Atrogin 1 and Glb1), diabetes (RAGE and CD163), and lipid accumulation (CD36 and PPARγ) and those of FMOD and MSTN were examined in CTX-injected, aged, MSTN−/−, and high-fat diet (HFD) mice and in C2C12 myoblasts treated with ceramide or grown under adipogenic conditions. Results from CTX-injected mice and gene knockdown experiments in C2C12 cells suggested the involvement of FMOD during muscle regeneration and myoblast proliferation and differentiation. Downregulation of the FMOD gene in MSTN−/− mice, and MSTN upregulation and FMOD downregulation in FMOD and MSTN knockdown C2C12 cells, respectively, during their differentiation, suggested FMOD negatively regulates MSTN gene expression, and MSTN positively regulates FMOD gene expression. The results of our in vivo and in vitro experiments indicate FMOD inhibits muscle aging by negatively regulating MSTN gene expression or by suppressing the action of MSTN protein, and that MSTN promotes muscle aging by positively regulating the expressions of Atrogin1, CD36, and PPARγ genes in muscle.

The roles of growth factors and hormones in the regulation of muscle satellite cells for cultured meat production

“…Some natural compounds [95][96][97] and inhibitory peptides targeting MSTN [21,98], such as Ac-MIF1 and Ac-MIF2-NH2, have been reported to inhibit the effect of MSTN significantly and enhance cell proliferation [99]. Additionally, in vivo and in vitro data showed that FMOD prevents muscle aging by decreasing the activity of MSTN protein [92]. These findings indicate that MSTN gene sequence modification and MSTN inhibition are good strategies for the mass production of cultured meat from agricultural animals.…”

“…Myostatin (growth and development factor-8, MSTN) is present in SM, and muscle mass in MSTN-null mice was reported to be dramatically enhanced due to increased muscle fiber levels (hyperplasia) and sizes (hypertrophy) [91,92]. Furthermore, the double-muscled phenotype in cattle has been linked to the MSTN gene.…”

Myostatin and its Regulation: A Comprehensive Review of Myostatin Inhibiting Strategies

“…FMOD is known to be actively involved in the assembly of ECM and was recently reported to be a novel regulator of MSTN during myoblast differentiation by regulating the transcriptional activities of MSTN and other myogenic marker genes, which include myogenin (MYOG) and myosin light chain 2 (MYL2) ( Lee et al, 2016 ). FMOD suppresses muscle aging by negatively regulating the MSTN gene or reducing the action of MSTN protein, while MSTN promotes muscle aging by positively regulating the expressions of the Atrogin1, CD36, and PPAR genes in muscle tissues ( Lee et al, 2021a ).…”

Identification and Evaluation of Traditional Chinese Medicine Natural Compounds as Potential Myostatin Inhibitors: An In Silico Approach

“…We previously investigated a number of ECM proteins that are involved in the regulation of myogenesis, including FMOD [10,11], matrix Gla protein [12], and dermatopontin [13]. FMOD slows muscle aging by suppressing the MSTN gene or decreasing MSTN protein activity, whereas MSTN promotes muscle aging [14]. Co-immunoprecipitation studies revealed that FMOD interacts directly with MSTN during myoblast differentiation.…”