Kunz, Hawley

ABSTRACT Early-life nutrition profoundly influences long-term metabolic health, and breast milk not only provides nutrients but also conveys maternal signals shaping infant metabolic development. While postpartum exercise by lactating women benefits maternal health, its impact on milk-borne signaling remains largely undefined. Small extracellular vesicles (sEVs) in breast milk are key mediators of maternal–infant communication because of their selectively packaged bioactive cargo and resistance to infant digestive enzymes and acids, enabling delivery of their cargo to peripheral tissues. Here, we show that a single session of moderate-intensity postpartum aerobic exercise robustly increases human breast milk sEV concentration, which persists for multiple post-exercise milk collections. Exercise enriches breast milk with sEVs containing regulatory metabolic cargo (proteins, miRNAs, and metabolites), which translates into enhanced mitochondrial capacity in neonatal-stage cells. These findings implicate sEVs as an exercise-responsive signaling compartment in breast milk capable of connecting postpartum maternal physical activity to beneficial infant metabolic programming. Highlights Acute moderate-intensity exercise increases human breast milk sEV concentration The exercise-mediated sEV increase lasts for multiple subsequent milk expressions Exercise coordinates a multi-omic enrichment of sEVs in breast milk Exercised breast milk sEVs enhance mitochondrial respiration in UC-MSCs

Intermuscular adipose tissue (IMAT) accumulates in the lower leg musculature of healthy older adults. IMAT was negatively associated with the rate of glucose infusion during a hyperinsulinemic-euglycemic clamp and muscle oxidative capacity. Exercise training decreased IMAT to a greater extent in young compared with older adults. Together these data support the implication that IMAT accumulation is linked with metabolic derangements in older adults but the restorative potential of exercise in older adults needs further evaluation.

ABSTRACT Background The unfolded protein response (UPR) is a proteostatic process that is activated in response to endoplasmic reticulum stress. It is currently unclear how aging influences the chronic and adaptive UPR in human skeletal muscle. Here we determined the effect of aging on UPR activation at rest, in response to exercise, and the associations with muscle function. Methods Thirty young (20–35 yr) and 50 older (65–85 yr) individuals were enrolled. Vastus lateralis biopsies were performed at rest and 3 and 48 h after a single bout of resistance exercise. The abundance of UPR-related transcripts and proteins was measured by RNA sequencing and Western blotting, respectively. Fractional synthetic rates of muscle protein were determined by mass spectrometry after intravenous infusion of 13 C 6 phenylalanine. Results Older adults demonstrated elevated transcriptional and proteomic markers of UPR activation in resting muscle. Resting UPR gene expression was negatively associated with muscle strength and power in older adults. The UPR is similarly activated by acute resistance exercise in young and older adults and positively associated with muscle function but not the anabolic response to exercise. Conclusions Skeletal muscle from older adults exhibits chronically activated UPR, which accompanies functional decline. The adaptive UPR is a proteostatic mechanism that is upregulated in response to exercise in young and older adults and positively associated with muscle function.

Abstract The loss of skeletal muscle mass during aging is a significant health concern linked to adverse outcomes in older individuals. Understanding the molecular basis of age‐related muscle loss is crucial for developing strategies to combat this debilitating condition. Long noncoding RNAs (lncRNAs) are a largely uncharacterized class of biomolecules that have been implicated in cellular homeostasis and dysfunction across a many tissues and cell types. To identify lncRNAs that might contribute to skeletal muscle aging, we screened for lncRNAs whose expression was altered in vastus lateralis muscle from older compared to young adults. We identified FRAIL1 as an aging‐induced lncRNA with high abundance in human skeletal muscle. In healthy young and older adults, skeletal muscle FRAIL1 was increased with age in conjunction with lower muscle function. Forced expression of FRAIL1 in mouse tibialis anterior muscle elicits a dose‐dependent reduction in skeletal muscle fiber size that is independent of changes in muscle fiber type. Furthermore, this reduction in muscle size is dependent on an intact region of FRAIL1 that is highly conserved across non‐human primates. Unbiased transcriptional and proteomic profiling of the effects of FRAIL1 expression in mouse skeletal muscle revealed widespread changes in mRNA and protein abundance that recapitulate age‐related changes in pathways and processes that are known to be altered in aging skeletal muscle. Taken together, these findings shed light on the intricate molecular mechanisms underlying skeletal muscle aging and implicate FRAIL1 in age‐related skeletal muscle phenotypes.

Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle–specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.

Abstract Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well‐studied. The purpose of this study was to investigate how obesity influences acute exercise responsiveness in skeletal muscle and circulating amino metabolites. Non‐obese (NO; n = 19; 10F/9M; BMI = 25.1 ± 2.8 kg/m 2 ) and Obese (O; n = 21; 14F/7M; BMI = 37.3 ± 4.6 kg/m 2 ) adults performed 30 min of single‐leg cycling at 70% of VO 2 peak. 13 C 6 ‐Phenylalanine was administered intravenously for muscle protein synthesis measurements. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3.5‐ and 6.5‐h post‐exercise to measure protein synthesis and gene expression. Targeted plasma metabolomics was used to quantitate amino metabolites before and 30 and 90 min after exercise. The exercise‐induced fold change in mixed muscle protein synthesis trended ( p = 0.058) higher in NO (1.28 ± 0.54‐fold) compared to O (0.95 ± 0.42‐fold) and was inversely related to BMI (R 2 = 0.140, p = 0.027). RNA sequencing revealed 331 and 280 genes that were differentially expressed after exercise in NO and O, respectively. Gene set enrichment analysis showed O had six blunted pathways related to metabolism, cell to cell communication, and protein turnover after exercise. The circulating amine response further highlighted dysregulations related to protein synthesis and metabolism in adults with obesity at the basal state and in response to the exercise bout. Collectively, these data highlight several unique pathways in individuals with obesity that resulted in a modestly blunted exercise response.