Metformin Delays Satellite Cell Activation and Maintains Quiescence

Abstract

The regeneration of the muscle tissue relies on the capacity of the satellite stem cell (SC) population to exit quiescence, divide asymmetrically, proliferate, and differentiate. In age-related muscle atrophy (sarcopenia) and several dystrophies, regeneration cannot compensate for the loss of muscle tissue. These disorders are associated with the depletion of the satellite cell pool or with the loss of satellite cell functionality. Recently, the establishment and maintenance of quiescence in satellite cells have been linked to their metabolic state. In this work, we aimed to modulate metabolism in order to preserve the satellite cell pool. We made use of metformin, a calorie restriction mimicking drug, to ask whether metformin has an effect on quiescence, proliferation, and differentiation of satellite cells. We report that satellite cells, when treated with metformin in vitro, ex vivo, or in vivo, delay activation, Pax7 downregulation, and terminal myogenic differentiation. We correlate the metformin-induced delay in satellite cell activation with the inhibition of the ribosome protein RPS6, one of the downstream effectors of the mTOR pathway. Moreover, in vivo administration of metformin induces a belated regeneration of cardiotoxin- (CTX-) damaged skeletal muscle. Interestingly, satellite cells treated with metformin immediately after isolation are smaller in size and exhibit reduced pyronin Y levels, which suggests that metformin-treated satellite cells are transcriptionally less active. Thus, our study suggests that metformin delays satellite cell activation and differentiation by favoring a quiescent, low metabolic state.

Metformin alleviates muscle wasting post-thermal injury by increasing Pax7-positive muscle progenitor cells

“…Therefore, it is plausible that metformin treatment provides more energy to proliferating satellite cells thus enhancing their ability to regenerate and repair damaged myofibers after burn injury. Recently, Pavlidou et al reported that metformin reduced the number of Pax7 + /BrdU + muscle progenitor cells and depleted skeletal muscle regeneration, a finding contrary to ours [75]. The differences between the two studies may be the nature of the injury.…”

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

“…Freshly isolated satellite cells were plated at a density of 15,000 cells/cm 2 on matrigel-coated 96-well plates at 37 °C and 5% CO 2 in satellite cell Growth Medium (sGM) composed of DMEM, 20% FBS, 10% Horse Serum (Euroclone, #ECS0090D), 2% Chicken Embryo Extract (Seralab, # CE-650-J) 65 . Prior to starting any experiment, freshly isolated SCs were cultured for at least 48 hours before treatment to allow cell adhesion.…”

“The Social Network” and Muscular Dystrophies: The Lesson Learnt about the Niche Environment as a Target for Therapeutic Strategies

“…Chronic inflammation is a typical hallmark of DMD and may contribute to impaired skeletal muscle regeneration. Although many cells are involved in chronic inflammation, one of the most important roles is played by macrophages, since these cells are associated not only to satellite cells’ activation but also to the survival of fibro/adipogenic progenitors (FAPs), which outcompete the satellite cell population during inflammation [ 44 ]. By competing with satellite cells, FAPs can increment the fibrotic process; an imbalance between the two populations ultimately leads to the accumulation of FAPs in skeletal muscles with consequent aberrant production of pro-fibrotic factors (e.g., ECM components).…”

“…Then, it is feasible that the molecular mechanism underlying the anti-fibrotic action (still under clarification for MET) or other parallel mechanisms can define the outcome on regeneration efficiency [ 121 ]. Interestingly, Pavlidou et al recently reported that, in C57BL/6 mice, MET delayed satellite cell activation and maintained quiescence (as shown by reduced Pax7 protein expression) [ 44 ].…”