Assessing the Utility of an Outpatient Exercise Program for Children With Cystic Fibrosis: A Quality Improvement Project

Children with cystic fibrosis (CF) (cwCF) suffer from inadequate weight gain, failure to thrive, and muscle weakness. The latter may be secondary to disuse atrophy (muscle wasting or reduction in muscle size associated with reduced physical activity and inflammation). Handgrip strength (HGS) is a reliable surrogate for muscle strength and lean body mass. Data from our CF center have shown an association between low HGS and forced expiratory volume in 1 s (FEV1) in cwCF. High-intensity interval training (HIIT) improves physical strength. Therefore, we devised a project to assess implementing a HIIT exercise program in the home setting, in order to improve physical strength in cwCF with HGS ≤ 50th percentile. Patients were instructed to complete 3–5 sessions of HIIT exercises per week. Wilcoxon matched-pairs signed-rank tests were used to compare HGS, FEV1, and body mass index (BMI) percentile at baseline and at a follow-up clinic visit. Follow-up was limited due to the COVID pandemic. Adherence to the HIIT regimen was poor. A total of twenty-nine cwCF participated in the program. However, a total of 13 individuals reported some form of moderate activity at follow-up and therefore constituted our final study population. There was a statistically significant increase in absolute grip strength (AGS) and FEV1 for these individuals. Even though the home HIIT protocol was not followed, the project demonstrated that moderate physical activity in cwCF can lead to significant improvement in HGS and overall physical strength.

Determinants of whole-body maximal aerobic performance in young male and female athletes: The roles of lower extremity muscle size, strength and power

This study sought to determine whether lower extremity muscle size, power and strength could be a determinant of whole-body maximal aerobic performance in athletes. 20 male and 19 female young athletes (18 ± 4 years) from various sporting disciplines participated in this study. All athletes performed a continuous ramp-incremental cycling to exhaustion for the determination of peak oxygen uptake (V˙O2peak: the highest V˙O2 over a 15-s period) and maximal power output (MPO: power output corresponding to V˙O2peak). Axial scanning of the right leg was performed with magnetic resonance imaging, and anatomical cross-sectional areas (CSAs) of quadriceps femoris (QF) and hamstring muscles at 50% of thigh length were measured. Moreover, bilateral leg extension power and unilateral isometric knee extension and flexion torque were determined. All variables were normalised to body mass, and six independent variables (V˙O2peak, CSAs of thigh muscles, leg extension power and knee extension and flexion torque) were entered into a forward stepwise multiple regression model with MPO being dependent variable for males and females separately. In the males, V˙O2peak was chosen as the single predictor of MPO explaining 78% of the variance. In the females, MPO was attributed to, in the order of importance, V˙O2peak (p < 0.001) and the CSA of QF (p = 0.011) accounting for 84% of the variance. This study suggests that while oxygen transport capacity is the main determinant of MPO regardless of sex, thigh muscle size also has a role in whole-body maximal aerobic performance in female athletes.

The m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice

Skeletal muscle serves fundamental roles in organismal health. Gene expression fluctuations are critical for muscle homeostasis and the response to environmental insults. Yet, little is known about post-transcriptional mechanisms regulating such fluctuations while impacting muscle proteome. Here we report genome-wide analysis of mRNA methyladenosine (m6A) dynamics of skeletal muscle hypertrophic growth following overload-induced stress. We show that increases in METTL3 (the m6A enzyme), and concomitantly m6A, control skeletal muscle size during hypertrophy; exogenous delivery of METTL3 induces skeletal muscle growth, even without external triggers. We also show that METTL3 represses activin type 2 A receptors (ACVR2A) synthesis, blunting activation of anti-hypertrophic signaling. Notably, myofiber-specific conditional genetic deletion of METTL3 caused spontaneous muscle wasting over time and abrogated overload-induced hypertrophy; a phenotype reverted by co-administration of a myostatin inhibitor. These studies identify a previously unrecognized post-transcriptional mechanism promoting the hypertrophic response of skeletal muscle via control of myostatin signaling.

Lack of variation in nuclear DNA content in avian muscle

The avian pectoralis muscle demonstrates plasticity with regard to size, so that temperate birds facing winter conditions or birds enduring a migration bout tend to have significant increases in the size and mass of this tissue due to muscular hypertrophy. Myonuclear domain (MND), the volume of cytoplasm a myonuclei services, in the pectoralis muscle of birds seems to be altered during thermal stress or changing seasons. However, there is no information available regarding muscle DNA content or ploidy level within the avian pectoralis. Changes in muscle DNA content can be used in this tissue to aid in size and mass changes. Here, we hypothesized that long-distance migrants or temperate residents would use the process of endoreduplication to aid in altering muscle size. Mostly contradictory to our hypotheses, we found no differences in the mean muscle DNA content in any of the 62 species of birds examined in this study. We also found no correlations between mean muscle DNA content and other muscle structural measurements, such as the number of nuclei per millimeter of fiber, myonuclear domain, and fiber cross-sectional area. Thus, while avian muscle seems more phenotypically plastic than mammalian muscle, the biological processes surrounding myonuclear function may be more closely related to those seen in mammals.

Efficacy of Exercise-Based Rehabilitation Programs for Improving Muscle Function and Size in People with Hip Osteoarthritis: A Systematic Review with Meta-Analysis

Objective: To determine the effect of exercise-based rehabilitation programs on hip and knee muscle function and size in people with hip osteoarthritis. Methods: Seven databases were systematically searched in order to identify studies that assessed muscle function (strength or power) and size in people with hip osteoarthritis after exercise-based rehabilitation programs. Studies were screened for eligibility and assessed for quality of evidence using the GRADE approach. Data were pooled, and meta-analyses was completed on 7 of the 11 included studies. Results: Six studies reported hip and/or knee function outcomes, and two reported muscle volumes that could be included in meta-analyses. Meta-analyses were conducted for four strength measures (hip abduction, hip extension, hip flexion, and knee extension) and muscle size (quadriceps femoris volume). For hip abduction, there was a low certainty of evidence with a small important effect (effect size = 0.28, 95% CI = 0.01, 0.54) favouring high-intensity resistance interventions compared to control. There were no other comparisons or overall meta-analyses that identified benefits for hip or knee muscle function or size. Conclusion: High-intensity resistance programs may increase hip abduction strength slightly when compared with a control group. No differences were identified in muscle function or size when comparing a high versus a low intensity group. It is unclear whether strength improvements identified in this review are associated with hypertrophy or other neuromuscular factors.

Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity.