Expansion capacity of human muscle progenitor cells differs by age, sex, and metabolic fuel preference

Abstract

Activation of satellite cells and expansion of the muscle progenitor cell (MPC) population is essential to generate a sufficient number of cells to repair damaged skeletal muscle. Proliferating MPCs have high energetic and biosynthetic material requirements, and the ability to utilize oxidative phosphorylation (OXPHOS) and/or glycolysis may affect expansion capacity of MPCs. In the present study, we investigated whether donor age and sex impact human MPC (hMPCs) expansion capacity and metabolic fuel preference. hMPCs from young and old males and females were grown for 408 h (17 days). Percent confluency, live nuclei count, and dead cell count were measured every 24 h. Metabolic phenotype was assessed using glucose uptake, expression of genes related to glycolysis and OXPHOS, and the Seahorse XF24 Phenotype Test Kit during the exponential phase of growth. hMPCs from old male donors had impaired expansion capacity secondary to heightened cell death early in expansion compared to hMPCs from young male donors, an effect not observed in female hMPCs. Age-related differences in metabolism were also sex-dependent; markers of OXPHOS were altered in old (vs. young) male hMPCs while markers of metabolism were largely unaffected by age in female hMPCs. For the first time, we identify sex-specific differences in cell death and OXPHOS that contribute to altered expansion capacity of hMPC cell populations with age.

Characterization of Skeletal Muscle Endocrine Control in an In Vitro Model of Myogenesis

“…The last decade has been an exciting period for the study of the biology of skeletal muscle stem cells and tissue regeneration and the development of novel human in vitro cell models can contribute to the identification of new mechanisms that control myogenesis [14][15][16][17][18][19][20]. These human cell cultures appear more suitable for predictive screening strategies when compared to rodent cell lines, such as C2C12 or rat L6 myoblasts [21,22].…”

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

“…In the present study, we demonstrated that USP2 contributes to the generation of sufficient ATP by OXPHOS in myoblasts. On the other hand, Usp2 KO cells exhibited impairments in proliferation and differentiation, both of which require an adequate glucose‐derived energy supply by the mitochondria (Elkalaf et al, ; Riddle et al, ). Collectively, these results suggest that USP2 might control proliferation and differentiation in myoblasts through sustained activation of mitochondria.…”

“…Although myofibers preferentially obtain ATP by OXPHOS, satellite cells and myoblasts may acquire ATP predominantly by glycolysis (Leary et al, 1998;Sin et al, 2016;Wagatsuma and Sakuma, 2013). On the other hand, a previous study demonstrated that the differentiation and proliferation of myoblasts is highly dependent on both OXPHOS and glycolysis (Riddle et al, 2018). Therefore, activated myoblasts seem to utilize both OXPHOS and glycolysis for ATP supply.…”

Peptide YY (PYY) Is Expressed in Human Skeletal Muscle Tissue and Expanding Human Muscle Progenitor Cells

“…Young (21–40 years) and old adults (65–80 years) were recruited from the Ithaca, New York and Boone, North Carolina areas (participant characteristics in Supplementary Table S1) in a manner previously published (Riddle et al, 2018a,b). The Cornell University and Appalachian State University Institutional Review Boards approved the protocols.…”