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

Activation of satellite cells and expansion of the muscle progenitor cell (MPC) population are 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 the effect of donor age and sex on human (h)MPC expansion capacity and metabolic fuel preference. hMPCs from young and old male and female donors were grown for 408 h (17 days). Percent confluence, live nuclei count, and dead cell count were measured every 24 h. Metabolic phenotype was assessed by 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 with 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, whereas 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 impaired expansion capacity of hMPC cell populations with age.

Transcript profile distinguishes variability in human myogenic progenitor cell expansion capacity.

Primary human muscle progenitor cells (hMPCs) are commonly used to understand skeletal muscle biology, including the regenerative process. Variability from unknown origin in hMPC expansion capacity occurs independently of disease, age, or sex of the donor. We sought to determine the transcript profile that distinguishes hMPC cultures with greater expansion capacity and to identify biological underpinnings of these transcriptome profile differences. Sorted (CD56+/CD29+) hMPC cultures were clustered by unbiased, K-means cluster analysis into FAST and SLOW based on growth parameters (saturation density and population doubling time). FAST had greater expansion capacity indicated by significantly reduced population doubling time (-60%) and greater saturation density (+200%), nuclei area under the curve (AUC, +250%), and confluence AUC (+120%). Additionally, FAST had fewer % dead cells AUC (-44%, P < 0.05). RNA sequencing was conducted on RNA extracted during the expansion phase. Principal component analysis distinguished FAST and SLOW based on the transcript profiles. There were 2,205 differentially expressed genes (DEgenes) between FAST and SLOW (q value ≤ 0.05); 362 DEgenes met a more stringent cut-off (q value ≤ 0.001 and 2.0 fold-change). DEgene enrichment suggested FAST (vs. SLOW) had promotion of the cell cycle, reduced apoptosis and cellular senescence, and enhanced DNA replication. Novel (RABL6, IRGM1, and AREG) and known (FOXM1, CDKN1A, Rb) genes emerged as regulators of identified functional pathways. Collectively the data suggest that variation in hMPC expansion capacity occurs independently of age and sex and is driven, in part, by intrinsic mechanisms that support the cell cycle.

Understanding Age-Related Changes in Skeletal Muscle Metabolism: Differences Between Females and Males.

Skeletal muscle is the largest metabolic organ system in the human body. As such, metabolic dysfunction occurring in skeletal muscle impacts whole-body nutrient homeostasis. Macronutrient metabolism changes within the skeletal muscle with aging, and these changes are associated in part with age-related skeletal muscle remodeling. Moreover, age-related changes in skeletal muscle metabolism are affected differentially between males and females and are likely driven by changes in sex hormones. Intrinsic and extrinsic factors impact observed age-related changes and sex-related differences in skeletal muscle metabolism. Despite some support for sex-specific differences in skeletal muscle metabolism with aging, more research is necessary to identify underlying differences in mechanisms. Understanding sex-specific aging skeletal muscle will assist with the development of therapies to attenuate adverse metabolic and functional outcomes.

Amino acids in healthy aging skeletal muscle.

Life expectancy in the U.S. and globally continues to increase. Despite increased life expectancy quality of life is not enhanced, and older adults often experience chronic age-related disease and functional disability, including frailty. Additionally, changes in body composition such as the involuntary loss of skeletal muscle mass (i.e. sarcopenia) and subsequent increases in adipose tissue can augment disease and disability in this population. Furthermore, increased oxidative stress and decreased antioxidant concentrations may also lead to metabolic dysfunction in older adults. Specific amino acids, including leucine, cysteine and its derivative taurine, and arginine can play various roles in healthy aging, especially in regards to skeletal muscle health. Leucine and arginine play important roles in muscle protein synthesis and cell growth while cysteine and arginine play important roles in quenching oxidative stress. Evidence suggests that supplemental doses of each of these amino acids may improve the aging phenotype. However, additional research is required to establish the doses required to achieve positive outcomes in humans.

Intrauterine growth restriction increases TNF α and activates the unfolded protein response in male rat pups.

Intrauterine growth restriction (IUGR) programs adult disease, including obesity and insulin resistance. Our group previously demonstrated that IUGR dysregulates adipose deposition in male, but not female, weanling rats. Dysregulated adipose deposition is often accompanied by the release of proinflammatory signaling molecules, such as tumor necrosis factor alpha (TNF α ). TNF α contributes to adipocyte inflammation and impaired insulin signaling. TNF α has also been implicated in the activation of the unfolded protein response (UPR), which impairs insulin signaling. We hypothesized that, in male rat pups, IUGR would increase TNF α , TNFR1, and components of the UPR (Hspa5, ATF6, p-eIF2 α , and Ddit3) prior to the onset of obesity. We further hypothesized that impaired glucose tolerance would occur after the onset of adipose dysfunction in male IUGR rats. To test this hypothesis, we used a well-characterized rat model of uteroplacental insufficiency-induced IUGR. Our primary findings are that, in male rats, IUGR (1) increased circulating and adipose TNF α , (2) increased mRNA levels of UPR components as well as p-eIF2a, and (3) impaired glucose tolerance after observed TNF α increased and after UPR activation. We speculate that programmed dysregulation of TNF α and UPR contributed to the development of glucose intolerance in male IUGR rats.

A case report of recovery of menstrual function following a nutritional intervention in two exercising women with amenorrhea of varying duration.

Increasing caloric intake is a promising treatment for exercise-associated amenorrhea, but strategies have not been fully explored. The purpose of this case report was to compare and contrast the responses of two exercising women with amenorrhea of varying duration to an intervention of increased energy intake. Two exercising women with amenorrhea of short (3 months) and long (11 months) duration were chosen to demonstrate the impact of increased caloric intake on recovery of menstrual function and bone health. Repeated measures of dietary intake, eating behavior, body weight, body composition, bone mineral density, resting energy expenditure, exercise volume, serum metabolic hormones and markers of bone turnover, and daily urinary metabolites were obtained. Participant 1 was 19 years old and had a body mass index (BMI) of 20.4 kg/m(2) at baseline. She increased caloric intake by 276 kcal/day (1,155 kJ/day, 13%), on average, during the intervention, and her body mass increased by 4.2 kg (8%). Participant 2 was 24 years old and had a BMI of 19.7 kg/m(2). She increased caloric intake by 1,881 kcal/day (7,870 kJ/day, 27%) and increased body mass by 2.8 kg (5%). Resting energy expenditure, triiodothyronine, and leptin increased; whereas, ghrelin decreased in both women. Resumption of menses occurred 23 and 74 days into the intervention for the women with short-term and long-term amenorrhea, respectively. The onset of ovulation and regular cycles corresponded with changes in body weight. Recovery of menses coincided closely with increases in caloric intake, weight gain, and improvements in the metabolic environment; however, the nature of restoration of menstrual function differed between the women with short-term versus long-term amenorrhea.