A low-intensity lifelong exercise routine changes miRNA expression in aging and prevents osteosarcopenic obesity by modulating inflammation.

Osteosarcopenic obesity (OSO) has been associated with increase immobility, falls, fractures, and other dysfunctions, which could increase mortality risk during aging. However, its etiology remains unknown. Recent studies revealed that sedentarism, fat gain, and epigenetic regulators are critical in its development. One effective intervention to prevent and treat OSO is exercise. Therefore, in the present study, by keeping rats in conditions of sedentarism and others under a low-intensity exercise routine, we established an experimental model of OSO. We determined the degree of sarcopenia, obesity, and osteopenia at different ages and analyzed the miRNA expression during the lifespan using miRNA microarrays from gastrocnemius muscle. Interestingly microarrays results showed that there is a set of miRNAs that changed their expression with exercise. The pathway enrichment analysis showed that these miRNAs are strongly associated with immune regulation. Further inflammatory profiles with IL-6/IL-10 and TNF-α/IL-10 ratios showed that exercised rats presented a lower pro-inflammatory profile than sedentary rats. Also, the body fat gain in the sedentary group increased the inflammatory profile, ultimately leading to muscle dysfunction. Exercise prevented strength loss over time and maintained skeletal muscle functionality over time. Differential expression of miRNAs suggests that they might participate in this process by regulating the inflammatory response associated with aging, thus preventing the development of OSO.

Moderate exercise combined with metformin-treatment improves mitochondrial bioenergetics of the quadriceps muscle of old female Wistar rats.

Sarcopenia is a syndrome that leads to physical disability and that deteriorates elderly people´s life quality. The etiology of sarcopenia is multifactorial, but mitochondrial dysfunction plays a paramount role in this pathology. Our research group has shown that the combined treatment of metformin (MTF) and exercise has beneficial effects for preventing muscle loss and fat accumulation, by modulating the redox state. To get an insight into the mechanism of the combined treatment, the mitochondrial bioenergetics was studied in the mitochondria isolated from old female Wistar rats quadriceps muscles. The animals were divided into six groups; three performed exercise on a treadmill for 5 days/week for 20 months, and the other three were sedentary. Also, two groups of each were treated with MTF for 6 or 12 months. The rats were euthanized at 24 months. The mitochondria were isolated and supercomplexes formation along with oxygen consumption, ATP synthesis, and ROS generation were evaluated. Our results showed that the combined treatment for 12 months increased the complex I and IV activities associated with the supercomplexes, simultaneously, ATP synthesis increased while ROS production decreased, indicating a tightly coupled mitochondria. The role of exercise plus the MTF treatment against sarcopenia in old muscles is discussed.

Advances in Genetics and Epigenetic Alterations in Alzheimer's Disease: A Notion for Therapeutic Treatment.

Alzheimer's disease (AD) is a disabling neurodegenerative disorder that leads to long-term functional and cognitive impairment and greatly reduces life expectancy. Early genetic studies focused on tracking variations in genome-wide DNA sequences discovered several polymorphisms and novel susceptibility genes associated with AD. However, despite the numerous risk factors already identified, there is still no fully satisfactory explanation for the mechanisms underlying the onset of the disease. Also, as with other complex human diseases, the causes of low heritability are unclear. Epigenetic mechanisms, in which changes in gene expression do not depend on changes in genotype, have attracted considerable attention in recent years and are key to understanding the processes that influence age-related changes and various neurological diseases. With the recent use of massive sequencing techniques, methods for studying epigenome variations in AD have also evolved tremendously, allowing the discovery of differentially expressed disease traits under different conditions and experimental settings. This is important for understanding disease development and for unlocking new potential AD therapies. In this work, we outline the genomic and epigenomic components involved in the initiation and development of AD and identify potentially effective therapeutic targets for disease control.

Metformin and tBHQ Treatment Combined with an Exercise Regime Prevents Osteosarcopenic Obesity in Middle-Aged Wistar Female Rats.

Osteosarcopenic obesity (OSO) is characterized by bone density, mass, and muscle strength loss, in conjunction with adipose tissue increase. OSO impairs physical activity and mobility, provoking autonomy loss; also, it is known that augmenting body fat in the elderly decreases life expectancy. The main factors influencing this health deterioration are the inflammatory environment induced by adipose tissue and its infiltration into muscle tissue, which leads to oxidative stress generation. Currently, there are several treatments to delay OSO, among which exercise training stands out because it improves muscle fiber quality and quantity and decreases adipose tissue. We have recently demonstrated that the combined treatment between moderate exercise and metformin slows sarcopenia's onset by a mechanism that includes adipose reduction and REDOX regulation. On the other hand, tert-butylhydroquinone (tBHQ) is a well-known antioxidant that counteracts oxidative stress. Therefore, to slow down obesity's harmful effects on muscle mass and bone mineral density, we performed different interventions, including combining a Fartlek-type exercise routine with metformin and tBHQ administration, in a model of middle-aged female Wistar rats with obesity induced with a hypercaloric diet. Our results showed that the combined exercise-metformin-tBHQ treatment increased muscle mass and strength, decreased body weight, body mass index, and fat percentage, and improved redox status, thus increasing animal survival.

Low-Intensity Exercise Routine for a Long Period of Time Prevents Osteosarcopenic Obesity in Sedentary Old Female Rats, by Decreasing Inflammation and Oxidative Stress and Increasing GDF-11.

The loss of skeletal muscle mass and strength is known as sarcopenia; it is characterized as a progressive and generalized muscle disorder associated with aging. This deterioration can seriously compromise the elderly's health and reduce their quality of life. In addition to age, there are other factors that induce muscle mass loss, among which are sedentary lifestyle, chronic diseases, inflammation, and obesity. In recent years, a new clinical condition has been observed in older adults that affects their physical capacities and quality of life, which is known as osteosarcopenic obesity (OSO). Osteoporosis, sarcopenia, and obesity coexist in this condition. Physical exercise and nutritional management are the most widely used interventions for the treatment and prevention of sarcopenia. However, in older adults, physical exercise and protein intake do not have the same outcomes observed in younger people. Here, we used a low-intensity exercise routine for a long period of time (LIERLT) in order to delay the OSO appearance related to sedentarism and aging in female Wistar rats. The LIERLT routine consisted of walking at 15 m/min for 30 min, five days a week for 20 months. To evaluate the effects of the LIERLT routine, body composition was determined using DXA-scan, additionally, biochemical parameters, inflammatory profile, oxidative protein damage, redox state, and serum concentration of GDF-11 at different ages were evaluated (4, 8, 12, 18, 22, and 24 months). Our results show that the LIERLT routine delays OSO phenotype in old 24-month-old rats, in a mechanism involving the decrease in the inflammatory state and oxidative stress. GDF-11 was evaluated as a protein related to muscle repair and regeneration; interestingly, rats that perform the LIERLT increased their GDF-11 levels.

Long-Term Moderate Exercise Combined with Metformin Treatment Induces an Hormetic Response That Prevents Strength and Muscle Mass Loss in Old Female Wistar Rats.

Sarcopenia is a syndrome characterized by a progressive and generalized skeletal muscle mass and strength loss, as well as a poor physical performance, which as strongly been associated with aging. Sedentary lifestyle in the elderly contributes to this condition; however, physical activity improves health, reducing morbidity and mortality. Recent studies have shown that metformin (MTF) can also prevent muscle damage promoting muscular performance. To date, there is great controversy if MTF treatment combined with exercise training improves or nullifies the benefits provided by physical activity. This study is aimed at evaluating the effect of long-term moderate exercise combined with MTF treatment on body composition, strength, redox state, and survival rate during the life of female Wistar rats. In this study, rats performed moderate exercise during 20 of their 24 months of life and were treated with MTF for one year or for 6 months, i.e., from 12 to 24 months old and 18 to 24 months old. The body composition (percentage of fat, bone, and lean mass) was determined using a dual-energy X-ray absorption scanner (DXA), and grip strength was determined using a dynamometer. Likewise, medial and tibial nerve somatosensory evoked potentials were evaluated and the redox state was measured by HPLC, calculating the GSH/GSSG ratio in the gastrocnemius muscle. Our results suggest- that the MTF administration, both in the sedentary and the exercise groups, might activate a mechanism that is directly related to the induction of the hormetic response through the redox state modulation. MTF treatment does not eliminate the beneficial effects of exercise throughout life, and although MTF does not increase muscle mass, it increases longevity.