Biological sex divergence in transcriptomic profiles during the onset of hindlimb unloading-induced atrophy.

Disuse-induced muscle atrophy is a common clinical problem observed mainly in older adults, intensive care units patients, or astronauts. Previous studies presented biological sex divergence in progression of disuse-induced atrophy along with differential changes in molecular mechanisms possibly underlying muscle atrophy. The aim of this study was to perform transcriptomic profiling of male and female mice during the onset and progression of unloading disuse-induced atrophy. Male and female mice underwent hindlimb unloading (HU) for 24, 48, 72, and 168 h (n = 8/group). Muscles were weighed for each cohort and gastrocnemius was used for RNA-sequencing analysis. Females exhibited muscle loss as early as 24 h of HU, whereas males after 168 h of HU. In males, pathways related to proteasome degradation were upregulated throughout 168 h of HU, whereas in females these pathways were upregulated up to 72 h of HU. Lcn2, a gene contributing to regulation of myogenesis, was upregulated by 6.46- to 19.86-fold across all time points in females only. A reverse expression of Fosb, a gene related to muscle degeneration, was observed between males (4.27-fold up) and females (4.57-fold down) at 24-h HU. Mitochondrial pathways related to tricarboxylic acid (TCA) cycle were highly downregulated at 168 h of HU in males, whereas in females this downregulation was less pronounced. Collagen-related pathways were consistently downregulated throughout 168 h of HU only in females, suggesting a potential biological sex-specific protective mechanism against disuse-induced fibrosis. In conclusion, females may have protection against HU-induced skeletal muscle mitochondrial degeneration and fibrosis through transcriptional mechanisms, although they may be more vulnerable to HU-induced muscle wasting compared with males.NEW & NOTEWORTHY Herein, we have assessed the transcriptomic response across biological sexes during the onset and progression of unloading disuse-induced atrophy in mice. We have demonstrated an inverse expression of Fosb between males and females, as well as differentially timed patterns of expressing atrophy-related pathways between sexes that are concomitant to the accelerated atrophy in females. We also identified in females signs of mechanisms to combat disuse-induced mitochondrial degeneration and fibrosis.

Females display relatively preserved muscle quality compared with males during the onset and early stages of C26-induced cancer cachexia.

Cancer cachexia is clinically defined by involuntary weight loss >5% in <6 mo, primarily affecting skeletal muscle. Here, we aimed to identify sex differences in the onset of colorectal cancer cachexia with specific consideration to skeletal muscle contractile and metabolic functions. Eight-weeks old BALB/c mice (69 males, 59 females) received subcutaneous C26 allografts or PBS vehicle. Tumors were developed for 10-, 15-, 20-, or 25 days. Muscles and organs were collected, in vivo muscle contractility, protein synthesis rate, mitochondrial function, and protein turnover markers were assessed. One-way ANOVA within sex and trend analysis between sexes were performed, P < 0.05. Gastrocnemius and tibialis anterior (TA) muscles became atrophic in male mice at 25 days, whereas female mice exhibited no significant differences in muscle weights at endpoints despite presenting hallmarks of cancer cachexia (fat loss, hepatosplenomegaly). We observed lowered muscle contractility and protein synthesis concomitantly to muscle mass decay in males, with higher proteolytic markers in muscles of both sexes. mRNA of Opa1 was lower in TA, whereas Bnip3 was higher in gastrocnemius after 25 days in male mice, with no significant effect in female mice. Our data suggest relative protections to skeletal muscle in females compared with males despite other canonical signs of cancer cachexia and increased protein degradation markers; suggesting we should place onus upon nonmuscle tissues during early stages of cancer cachexia in females. We noted potential protective mechanisms relating to skeletal muscle contractile and mitochondrial functions. Our findings underline possible heterogeneity in onset of cancer cachexia between biological sexes, suggesting the need for sex-specific approaches to treat cancer cachexia.NEW & NOTEWORTHY Our study demonstrates biological-sex differences in phenotypic characteristics of cancer cachexia between male and female mice, whereby females display many common characteristics of cachexia (gonadal fat loss and hepatosplenomegaly), protein synthesis markers alterations, and common catabolic markers in skeletal muscle despite relatively preserved muscle mass in early-stage cachexia compared with males. Mechanisms of cancer cachexia appear to differ between sexes. Data suggest need to place onus of early cancer cachexia detection and treatment on nonmuscle tissues in females.

Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress.

Muscle weakness and wasting are defining features of cancer-induced cachexia. Mitochondrial stress occurs before atrophy in certain muscles, but the possibility of heterogeneous responses between muscles and across time remains unclear. Using mice inoculated with Colon-26 cancer, we demonstrate that specific force production was reduced in quadriceps and diaphragm at 2 weeks in the absence of atrophy. At this time, pyruvate-supported mitochondrial respiration was lower in quadriceps while mitochondrial H2O2 emission was elevated in diaphragm. By 4 weeks, atrophy occurred in both muscles, but specific force production increased to control levels in quadriceps such that reductions in absolute force were due entirely to atrophy. Specific force production remained reduced in diaphragm. Mitochondrial respiration increased and H2O2 emission was unchanged in both muscles versus control while mitochondrial creatine sensitivity was reduced in quadriceps. These findings indicate muscle weakness precedes atrophy and is linked to heterogeneous mitochondrial alterations that could involve adaptive responses to metabolic stress. Eventual muscle-specific restorations in specific force and bioenergetics highlight how the effects of cancer on one muscle do not predict the response in another muscle. Exploring heterogeneous responses of muscle to cancer may reveal new mechanisms underlying distinct sensitivities, or resistance, to cancer cachexia.

Exercise Counteracts the Deleterious Effects of Cancer Cachexia.

Cancer cachexia (CC) is a multifactorial syndrome characterised by unintentional loss of body weight and muscle mass in patients with cancer. The major hallmarks associated with CC development and progression include imbalanced protein turnover, inflammatory signalling, mitochondrial dysfunction and satellite cell dysregulation. So far, there is no effective treatment to counteract muscle wasting in patients with CC. Exercise training has been proposed as a potential therapeutic approach for CC. This review provides an overview of the effects of exercise training in CC-related mechanisms as well as how factors such as cancer comorbidities, exercise modality and biological sex can influence exercise effectiveness in CC. Evidence in mice and humans suggests exercise training combats all of the hallmarks of CC. Several exercise modalities induce beneficial adaptations in patients/animals with CC, but concurrent resistance and endurance training is considered the optimal type of exercise. In the case of cancer patients presenting comorbidities, exercise training should be performed only under specific guidelines and precautions to avoid adverse effects. Observational comparison of studies in CC using different biological sex shows exercise-induced adaptations are similar between male and female patients/animals with cancer, but further studies are needed to confirm this.

miR-23a suppression accelerates functional decline in the rNLS8 mouse model of TDP-43 proteinopathy.

Skeletal muscle dysfunction may contribute to the progression and severity of amyotrophic lateral sclerosis (ALS). In the present study, we characterized the skeletal muscle pathophysiology in an inducible transgenic mouse model (rNLS8) that develops a TAR-DNA binding protein (TDP-43) proteinopathy and ALS-like neuropathology and disease progression; representative of >90% of all familial and sporadic ALS cases. As we previously observed elevated levels of miR-23a in skeletal muscle of patients with familial and sporadic ALS, we also investigated the effect of miR-23a suppression on skeletal muscle pathophysiology and disease severity in rNLS8 mice. Five weeks after disease onset TDP-43 protein accumulation was observed in tibialis anterior (TA), quadriceps (QUAD) and diaphragm muscle lysates and associated with skeletal muscle atrophy. In the TA muscle TDP-43 was detected in muscle fibres that appeared atrophied and angular in appearance and that also contained ß-amyloid aggregates. These fibres were also positive for neural cell adhesion molecule (NCAM), but not embryonic myosin heavy chain (eMHC), indicating TDP-43/ ß-amyloid localization in denervated muscle fibres. There was an upregulation of genes associated with myogenesis and NMJ degeneration and a decrease in the MURF1 atrophy-related protein in skeletal muscle. Suppression of miR-23a impaired rotarod performance and grip strength and accelerated body weight loss during early stages of disease progression. This was associated with increased AchRα mRNA expression and decreased protein levels of PGC-1α. The TDP-43 proteinopathy-induced impairment of whole body and skeletal muscle functional performance is associated with muscle wasting and elevated myogenic and NMJ stress markers. Suppressing miR-23a in the rNLS8 mouse model of ALS contributes to an early acceleration of disease progression as measured by decline in motor function.

The Role of Exercise as a Non-pharmacological Therapeutic Approach for Amyotrophic Lateral Sclerosis: Beneficial or Detrimental?

Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, involves the rapid deterioration of motor neurons resulting in severe muscle atrophy and respiratory insufficiency. It is considered a "multisystemic" disease with many potential mechanisms responsible for its pathology. Currently, there is no cure for ALS. Exercise training is suggested as a potential approach to reduce ALS pathology, but its beneficial role remains controversial. This review provides an overview of the effects of exercise training in ALS-affected mice and patients. It will compare the intensity, duration, and type of exercise on the health of SOD1G93A mice, a mouse model of familial ALS, and review clinical studies involving ALS patients undergoing both endurance and resistance training. In summary, mild-to-moderate swimming-based endurance training appears the most advantageous mode of exercise in SOD1G93A mice, improving animal survival, and delaying the onset and progression of disease. Furthermore, clinical studies show that both endurance and resistance training have an advantageous impact on the quality of life of ALS patients without extending life expectancy. However, small sample sizes, non-representative control populations, heterogeneous disease stage of patients, and the presence of confounders often exist in the exercise studies conducted with ALS patients. This raises concerns about the interpretation of these findings and, therefore, these results should be considered with caution. While promising, more pre-clinical and clinical studies with improved experimental design and fewer limitations are still necessary to confirm the impact of exercise training on the health of ALS patients.

Skeletal Muscle Satellite Cells, Mitochondria, and MicroRNAs: Their Involvement in the Pathogenesis of ALS.

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal motor neuron disorder. It results in progressive degeneration and death of upper and lower motor neurons, protein aggregation, severe muscle atrophy and respiratory insufficiency. Median survival with ALS is between 2 and 5 years from the onset of symptoms. ALS manifests as either familial ALS (FALS) (~10% of cases) or sporadic ALS (SALS), (~90% of cases). Mutations in the copper/zinc (CuZn) superoxide dismutase (SOD1) gene account for ~20% of FALS cases and the mutant SOD1 mouse model has been used extensively to help understand the ALS pathology. As the precise mechanisms causing ALS are not well understood there is presently no cure. Recent evidence suggests that motor neuron degradation may involve a cell non-autonomous phenomenon involving numerous cell types within various tissues. Skeletal muscle is now considered as an important tissue involved in the pathogenesis of ALS by activating a retrograde signaling cascade that degrades motor neurons. Skeletal muscle heath and function are regulated by numerous factors including satellite cells, mitochondria and microRNAs. Studies demonstrate that in ALS these factors show various levels of dysregulation within the skeletal muscle. This review provides an overview of their dysregulation in various ALS models as well as how they may contribute individually and/or synergistically to the ALS pathogenesis.

The Acute Impact of Different Types of Aerobic Exercise on Arterial Wave Reflections and Inflammation.

OBJECTIVES: Whilst physical activity is linked to cardiovascular health, it has lately been recognized that different types of exercise exert diverse effects on the cardiovascular system. Therefore, we investigated the acute effects of continuous moderate-intensity aerobic exercise (CAE) and high-intensity interval aerobic exercise (hIAE) on arterial function and inflammation. METHODS: Twenty healthy men (mean age 22.6 ± 3.3 years) were recruited in this crossover study. Each of the 20 volunteers participated in two separate sessions (hIAE and CAE). The augmentation index (AIx) of aortic pressure waveforms and serum levels of interleukin-17 (IL-17) were measured before and after each exercise session. RESULTS: There were no significant differences in baseline hemodynamic and inflammatory measurements before CAE and hIAE. Compared to baseline, AIx was significantly improved after CAE (p = 0.04), while there was no significant change after hIAE (p = 0.65). Serum levels of IL-17 were significantly elevated after CAE (p = 0.042), while hIAE had no significant effect on IL-17 levels (p = 0.47). Interestingly, there was an inverse association between the elevation of IL-17 levels and the AIx improvement after CAE (p = 0.05). CONCLUSION: These findings provide additional evidence concerning the cardiovascular effects of different types of exercise training through modification of peripheral hemodynamics and the inflammatory process.

Acute effects of different types of aerobic exercise on endothelial function and arterial stiffness.

BACKGROUND: Chronic aerobic exercise training is associated with improved endothelial function and arterial stiffness and favourable long-term cardiovascular effects. DESIGN: We investigated the acute effects of continuous moderate intensity aerobic exercise (CAE) and high intensity interval aerobic exercise (hIAE) on endothelial function and arterial stiffness in healthy participants. METHODS: Twenty healthy men were recruited to this cross-over study. They participated in two exercise sessions: (a) CAE, volume at 50% of maximum aerobic work for 30 minutes; and (b) hIAE, interval maximum aerobic work for 30 minutes. Endothelial function was evaluated by flow-mediated dilation in the brachial artery. The carotid femoral pulse wave velocity and the femoral dorsalis pedis pulse wave velocity were measured as indices of central aortic and peripheral arterial stiffness. Measurements were carried out before and immediately after each exercise session. RESULTS: There was no statistically significant difference in the baseline measurements before CAE and hIAE with respect to flow-mediated dilation, the carotid femoral pulse wave velocity and the femoral dorsalis pedis pulse wave velocity (p = NS). Both CAE and hIAE significantly improved the flow-mediated dilation compared with baseline (p < 0.001). Similarly, the femoral dorsalis pedis pulse wave velocity was improved after CAE and hIAE (p < 0.005), whereas the carotid femoral pulse wave velocity was not significantly affected (p = NS). CONCLUSION: Both CAE and hIAE can favourably affect endothelial function, suggesting another cardioprotective effect of acute exercise. These types of aerobic exercise have a different impact on the central and peripheral arterial stiffness.