Murine exercise models can provide information on factors that influence muscle adaptability with aging, but few translatable solutions exist. Progressive weighted wheel running (PoWeR) is a simple, voluntary, low-cost, high-volume endurance/resistance exercise approach for training young mice. In the current investigation, aged mice (22-month-old) underwent a modified version of PoWeR for 8 weeks. Muscle functional, cellular, biochemical, transcriptional, and myonuclear DNA methylation analyses provide an encompassing picture of how muscle from aged mice responds to high-volume combined training. Mice run 6-8 km/day, and relative to sedentary mice, PoWeR increases plantarflexor muscle strength. The oxidative soleus of aged mice responds to PoWeR similarly to young mice in every parameter measured in previous work; this includes muscle mass, glycolytic-to-oxidative fiber type transitioning, fiber size, satellite cell frequency, and myonuclear number. The oxidative/glycolytic plantaris adapts according to fiber type, but with modest overall changes in muscle mass. Capillarity increases markedly with PoWeR in both muscles, which may be permissive for adaptability in advanced age. Comparison to published PoWeR RNA-sequencing data in young mice identified conserved regulators of adaptability across age and muscles; this includes Aldh1l1 which associates with muscle vasculature. Agrn and Samd1 gene expression is upregulated after PoWeR simultaneous with a hypomethylated promoter CpG in myonuclear DNA, which could have implications for innervation and capillarization. A promoter CpG in Rbm10 is hypomethylated by late-life exercise in myonuclei, consistent with findings in muscle tissue. PoWeR and the data herein are a resource for uncovering cellular and molecular regulators of muscle adaptation with aging.

Vitamin D is an essential nutrient for the maintenance of skeletal muscle and bone health. The vitamin D receptor (VDR) is present in muscle, as is CYP27B1, the enzyme that hydroxylates 25(OH)D to its active form, 1,25(OH)D. Furthermore, mounting evidence suggests that vitamin D may play an important role during muscle damage and regeneration. Muscle damage is characterized by compromised muscle fiber architecture, disruption of contractile protein integrity, and mitochondrial dysfunction. Muscle regeneration is a complex process that involves restoration of mitochondrial function and activation of satellite cells (SC), the resident skeletal muscle stem cells. VDR expression is strongly upregulated following injury, particularly in central nuclei and SCs in animal models of muscle injury. Mechanistic studies provide some insight into the possible role of vitamin D activity in injured muscle. In vitro and in vivo rodent studies show that vitamin D mitigates reactive oxygen species (ROS) production, augments antioxidant capacity, and prevents oxidative stress, a common antagonist in muscle damage. Additionally, VDR knockdown results in decreased mitochondrial oxidative capacity and ATP production, suggesting that vitamin D is crucial for mitochondrial oxidative phosphorylation capacity; an important driver of muscle regeneration. Vitamin D regulation of mitochondrial health may also have implications for SC activity and self-renewal capacity, which could further affect muscle regeneration. However, the optimal timing, form and dose of vitamin D, as well as the mechanism by which vitamin D contributes to maintenance and restoration of muscle strength following injury, have not been determined. More research is needed to determine mechanistic action of 1,25(OH)D on mitochondria and SCs, as well as how this action manifests following muscle injury in vivo. Moreover, standardization in vitamin D sufficiency cut-points, time-course study of the efficacy of vitamin D administration, and comparison of multiple analogs of vitamin D are necessary to elucidate the potential of vitamin D as a significant contributor to muscle regeneration following injury. Here we will review the contribution of vitamin D to skeletal muscle regeneration following injury.

Background: Anterior cruciate ligament (ACL) tear (ACLT) leads to protracted quadriceps muscle atrophy. Protein turnover largely dictates muscle size and is highly responsive to injury and loading. Regulation of quadriceps molecular protein synthetic machinery after ACLT has largely been unexplored, limiting development of targeted therapies. Purpose: To define the effect of ACLT on (1) the activation of protein synthetic and catabolic signaling within quadriceps biopsy specimens from human participants and (2) the time course of alterations to protein synthesis and its molecular regulation in a mouse ACL injury model. Study Design: Descriptive laboratory study. Methods: Muscle biopsy specimens were obtained from the ACL-injured and noninjured vastus lateralis of young adult humans after an overnight fast (N = 21; mean ± SD, 19 ± 5 years). Mice had their limbs assigned to ACLT or control, and whole quadriceps were collected 6 hours or 1, 3, or 7 days after injury with puromycin injected before tissue collection for assessment of relative protein synthesis. Muscle fiber size and expression and phosphorylation of protein anabolic and catabolic signaling proteins were assessed at the protein and transcript levels (RNA sequencing). Results: Human quadriceps showed reduced phosphorylation of ribosomal protein S6 (–41%) in the ACL-injured limb ( P = .008), in addition to elevated phosphorylation of eukaryotic initiation factor 2α (+98%; P = .006), indicative of depressed protein anabolic signaling in the injured limb. No differences in E3 ubiquitin ligase expression were noted. Protein synthesis was lower at 1 day ( P = .01 vs control limb) and 3 days ( P = .002 vs control limb) after ACLT in mice. Pathway analyses revealed shared molecular alterations between human and mouse quadriceps after ACLT. Conclusion: (1) Global protein synthesis and anabolic signaling deficits occur in the quadriceps in response to ACL injury, without notable changes in measured markers of muscle protein catabolism. (2) Importantly, these deficits occur before the onset of significant atrophy, underscoring the need for early intervention. Clinical Relevance: These findings suggest that blunted protein anabolism as opposed to increased catabolism likely mediates quadriceps atrophy after ACL injury. Thus, future interventions should aim to restore muscle protein anabolism rapidly after ACLT.

Carbohydrate (CHO) ingestion is an established strategy to improve endurance performance. Race fuels should not only sustain performance but also be readily digested and absorbed. Potatoes are a whole-food-based option that fulfills these criteria, yet their impact on performance remains unexamined. We investigated the effects of potato purée ingestion during prolonged cycling on subsequent performance vs. commercial CHO gel or a water-only condition. Twelve cyclists (70.7 ± 7.7 kg, 173 ± 8 cm, 31 ± 9 yr, 22 ± 5.1% body fat; means ± SD) with average peak oxygen consumption (V̇o2peak) of 60.7 ± 9.0 mL·kg−1·min−1 performed a 2-h cycling challenge (60–85% V̇o2peak) followed by a time trial (TT; 6 kJ/kg body mass) while consuming potato, gel, or water in a randomized-crossover design. The race fuels were administered with [U-13C6]glucose for an indirect estimate of gastric emptying rate. Blood samples were collected throughout the trials. Blood glucose concentrations were higher ( P < 0.001) in potato and gel conditions compared with water condition. Blood lactate concentrations were higher ( P = 0.001) after the TT completion in both CHO conditions compared with water condition. TT performance was improved ( P = 0.032) in both potato (33.0 ± 4.5 min) and gel (33.0 ± 4.2 min) conditions compared with water condition (39.5 ± 7.9 min). Moreover, no difference was observed in TT performance between CHO conditions ( P = 1.00). In conclusion, potato and gel ingestion equally sustained blood glucose concentrations and TT performance. Our results support the effective use of potatoes to support race performance for trained cyclists. NEW & NOTEWORTHY The ingestion of concentrated carbohydrate gels during prolonged exercise has been shown to promote carbohydrate availability and improve exercise performance. Our study aim was to expand and diversify race fueling menus for athletes by providing an evidence-based whole-food alternative to the routine ingestion of gels during training and competition. Our work shows that russet potato ingestion during prolonged cycling is as effective as carbohydrate gels to support exercise performance in trained athletes.

Multinuclear muscle fibers are the most voluminous cells in skeletal muscle and the primary drivers of growth in response to loading. Outside the muscle fiber, however, is a diversity of mononuclear cell types that reside in the extracellular matrix (ECM). These muscle-resident cells are exercise-responsive and produce the scaffolding for successful myofbrillar growth. Without proper remodeling and maintenance of this ECM scaffolding, the ability to mount an appropriate response to resistance training in adult muscle is severely hindered. Complex cellular choreography takes place in muscle following a loading stimulus. These interactions have been recently revealed by single-cell explorations into muscle adaptation with loading. The intricate ballet of ECM remodeling involves collagen production from fibrogenic cells and ECM modifying signals initiated by satellite cells, immune cells, and the muscle fibers themselves. The acellular collagen-rich ECM is also a mechanical signal-transducer and rich repository of growth factors that may directly influence muscle fiber hypertrophy once liberated. Collectively, high levels of collagen expression, deposition, and turnover characterizes a well-trained muscle phenotype. The purpose of this review is to highlight the most recent evidence for how the ECM and its cellular components affect loading-induced muscle hypertrophy. We also address how the muscle fiber may directly take part in ECM remodeling, and whether ECM dynamics are rate-limiting for muscle fiber growth.