microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.

MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.

Satellite cell dynamics during skeletal muscle hypertrophy.

Skeletal muscle stem cells (MuSCs) display distinct behavior crucial for tissue maintenance and repair. Upon activation, MuSCs exhibit distinct modes of division: symmetric division, facilitating either self-renewal or differentiation, and asymmetric division, which dictates divergent cellular fates. This review explores the nuanced dynamics of MuSC division and the molecular mechanisms governing this behavior. Furthermore, it introduces a novel phenomenon observed in a subset of MuSCs under hypertrophic stimuli termed division-independent differentiation. Insights into the underlying mechanisms driving this process are discussed, alongside its broader implications for muscle physiology.

The utility of the rodent synergist ablation model in identifying molecular and cellular mechanisms of skeletal muscle hypertrophy.

Skeletal muscle exhibits remarkable plasticity to adapt to stimuli such as mechanical loading. The mechanisms that regulate skeletal muscle hypertrophy due to mechanical overload have been thoroughly studied. Remarkably, our understanding of many of the molecular and cellular mechanisms that regulate hypertrophic growth were first identified using the rodent synergist ablation (SA) model and subsequently corroborated in human resistance exercise training studies. To demonstrate the utility of the SA model, we briefly summarize the hypertrophic mechanisms identified using the model and the following translation of these mechanism to human skeletal muscle hypertrophy induced by resistance exercise training.

Skeletal muscle hypertrophy: cell growth is cell growth.

Roberts et al. have provided an insightful counterpoint to our review article on the utility of the synergist ablation model. The purpose of this review is to provide some further dialogue regarding the strengths and weaknesses of the synergist ablation model. Specifically, we highlight that the robustness of the model overshadows surgical limitations. We also compare the transcriptomic responses to synergist ablation in mice and resistance exercise in humans to identify common pathways. We conclude that "cell growth is cell growth" and that the mechanisms available to cells to accumulate biomass and increase in size are similar across cell types and independent of the rate of growth.

Microbial-Derived Exerkines Prevent Skeletal Muscle Atrophy.

Regular exercise yields a multitude of systemic benefits, many of which may be mediated through the gut microbiome. Here, we report that cecal microbial transplants (CMTs) from exercise-trained vs. sedentary mice have modest benefits in reducing skeletal muscle atrophy using a mouse model of unilaterally hindlimb-immobilization. Direct administration of top microbial-derived exerkines from an exercise-trained gut microbiome preserved muscle function and prevented skeletal muscle atrophy.

ApoE isoform does not influence skeletal muscle regeneration in adult mice.

Introduction: Apolipoprotein E (ApoE) has been shown to be necessary for proper skeletal muscle regeneration. Consistent with this finding, single-cell RNA-sequencing analyses of skeletal muscle stem cells (MuSCs) revealed that Apoe is a top marker of quiescent MuSCs that is downregulated upon activation. The purpose of this study was to determine if muscle regeneration is altered in mice which harbor one of the three common human ApoE isoforms, referred to as ApoE2, E3 and E4. Methods: Histomorphometric analyses were employed to assess muscle regeneration in ApoE2, E3, and E4 mice after 14 days of recovery from barium chloride-induced muscle damage in vivo, and primary MuSCs were isolated to assess proliferation and differentiation of ApoE2, E3, and E4 MuSCs in vitro. Results: There was no difference in the basal skeletal muscle phenotype of ApoE isoforms as evaluated by section area, myofiber cross-sectional area (CSA), and myonuclear and MuSC abundance per fiber. Although there were no differences in fiber-type frequency in the soleus, Type IIa relative frequency was significantly lower in plantaris muscles of ApoE4 mice compared to ApoE3. Moreover, ApoE isoform did not influence muscle regeneration as assessed by fiber frequency, fiber CSA, and myonuclear and MuSC abundance. Finally, there were no differences in the proliferative capacity or myogenic differentiation potential of MuSCs between any ApoE isoform. Discussion: Collectively, these data indicate nominal effects of ApoE isoform on the ability of skeletal muscle to regenerate following injury or the in vitro MuSC phenotype.

Two Days Versus Four Days of Training Cessation Following a Step-Taper in Powerlifters.

ABSTRACT: Burke, BI, Carroll, KM, Travis, SK, Stone, ME, and Stone, MH. Two days versus four days of training cessation following a step-taper in powerlifters. J Strength Cond Res 37(12): e625-e632, 2023-Tapering and training cessation are methods of training load management aimed at optimizing athlete preparedness leading into competition. Such practices are often used by strength sport athletes such as powerlifters (i.e., athletes who compete in the back squat [BS], bench press [BP], and deadlift [DL]). The purpose of this study was to compare the differences in maximal strength, subjective recovery and stress state, and body composition alterations in strength athletes undergoing a 1-week step-taper followed by either a 2-day (2D) or 4-day (4D) period of training cessation. Twelve powerlifters (22.3 ± 2.1 yrs; 92.1 ± 20.4 kg; 174.8 ± 7.5 cm) completed a 6-week training protocol aimed at peaking 1 repetition maximum (1RM) strength on BS, BP, and DL. Body composition, subjective recovery and stress state, and 1RM on BS, BP, and DL were assessed before an overreach week (T1) and after the periods of training cessation (T2) for each group. Alpha criterion was set at p ≤ 0.05. There were significant increases in BP ( p = 0.032, g = 0.10), powerlifting total ( p = 0.014, g = 0.11), and DOTS score ( p = 0.006, g = 0.12) after 2D of cessation. However, after 4D of cessation, significant increases were only observed in DL ( p = 0.019, g = 0.11) along with significant decreases in BP ( p = 0.003, g = -0.13). There were no statistically significant changes in any other variable for either group indicating that BS, psychometric, and body composition data were maintained between T1 and T2. The results of this study support the use of 1-week step-tapers, followed by a short period of training cessation (2-4D) to maintain or improve maximal strength performance.

The Effects of Caffeine on Jumping Performance and Maximal Strength in Female Collegiate Athletes.

Caffeine is often used in a variety of forms to enhance athletic performance; however, research regarding caffeine's effects on strength and power in female athletes is lacking. Therefore, the purpose of this study was to analyze the acute effects of caffeine anhydrous (6 mg/kg of body mass) on jumping performance and maximal strength in female collegiate athletes. Eleven athletes (19.7 ± 0.9 yrs; 166.4 ± 10.2 cm, 67.7 ± 9.4 kg) performed two testing sessions separated by one week, and randomly received caffeine or placebo using a double-blind approach. Heart rate, blood pressure, and tympanic temperature were recorded before athletes received each condition, following 60 min of quiet sitting, and directly after performance testing. Athletes were assessed on unweighted and weighted squat jump height (SJH0, SJH20) and countermovement jump height (CMJH0, CMJH20), isometric mid-thigh pull peak force (IPF), and rate of force development from 0-200 ms (RFD200). Resting systolic blood pressure was significantly greater following caffeine administration compared to a placebo (p = 0.017). There were small, significant differences in SJH0 (p = 0.035, g = 0.35), SJH20 (p = 0.002, g = 0.49), CMJH0 (p = 0.015, g = 0.19), and CMJH20 (p < 0.001, g = 0.37) in favor of caffeine over placebo. However, there was no significant difference in IPF (p = 0.369, g = 0.12) and RFD200 (p = 0.235, g = 0.32) between conditions. Therefore, caffeine appears to enhance jumping performance, but not maximal strength in female collegiate athletes.