Autophagy Signaling in Skeletal Muscle of Infarcted Rats (original) (raw)
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Autophagy in health and disease. 3. Involvement of autophagy in muscle atrophy
AJP: Cell Physiology, 2010
Loss of muscle mass aggravates a variety of diseases, and understanding the molecular mechanisms that control muscle wasting is critical for developing new therapeutic approaches. Weakness is caused by loss of muscle proteins, and recent studies have underlined a major role for the autophagy-lysosome system in regulating muscle mass. Some key components of the autophagy machinery are transcriptionally upregulated during muscle wasting, and their induction precedes muscle loss. However, it is unclear whether autophagy is detrimental, causing atrophy, or beneficial, promoting survival during catabolic conditions. This review discusses recent findings on signaling pathways regulating autophagy.
FEBS Letters, 2010
Muscle mass represents 40-50% of the human body and, in mammals, is one of the most important sites for the control of metabolism. Moreover, during catabolic conditions, muscle proteins are mobilized to sustain gluconeogenesis in the liver and to provide alternative energy substrates for organs. However, excessive protein degradation in the skeletal muscle is detrimental for the economy of the body and it can lead to death. The ubiquitin-proteasome and autophagy-lysosome systems are the major proteolytic pathways of the cell and are coordinately activated in atrophying muscles. However, the role and regulation of the autophagic pathway in skeletal muscle is still largely unknown. This review will focus on autophagy and discuss its beneficial or detrimental role for the maintenance of muscle mass.
Autophagy Is Required to Maintain Muscle Mass
Cell Metabolism, 2009
The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes for protein and organelle clearance. In skeletal muscle, both systems are under FoxO regulation and their excessive activation induces severe muscle loss. Although altered autophagy has been observed in various myopathies, the specific role of autophagy in skeletal muscle has not been determined by loss-of-function approaches.
Chapter 19 Monitoring Autophagy in Muscle Diseases
Methods in Enzymology, 2009
Autophagy is a tightly regulated pathway for the degradation and recycling of proteins delivered to lysosomes, and is an important process in maintaining cellular homeostasis. Whereas a basal level of autophagy can be detected in skeletal muscles, its perturbation can be seen in a variety of conditions affecting the muscle. In certain muscle diseases, moreover, autophagy seems to be a characteristic feature, although the exact role of autophagy in these disorders is just starting to be understood. As autophagy is not only an index of disease progression but also a potential target for treatment in certain disease conditions, its characterization is indeed of relevance. Thus, in this chapter, methods applicable to both human and murine skeletal muscle preparation for the analysis and monitoring of autophagy are presented.
Mitochondrial dysfunction and autophagy responses to skeletal muscle stress
2019
Autophagy plays an important role in mitochondrial maintenance, yet many details of skeletal muscle autophagic activity are unresolved in the context of muscle stress and/or damage. Skeletal muscles from mice were stressed either by fatiguing contractions, eccentric contractioninduced injury (ECCI), or freeze injury (FI) to establish a timeline of mitochondrial function and autophagy induction after different forms of muscle stress. Only FI was sufficient to elicit a reduction in mitochondrial function (-88%, p=0.006), yet both ECCI and FI resulted in greater autophagy-related protein content (28-fold, p0.008) suggesting a tunable autophagic response. Muscles from another cohort of mice were used to determine specific forms of autophagy, i.e., flux and mitochondrial-specific, in response to muscle damage. Mitochondrial-specific autophagy was evident by accumulation of autophagy-related proteins in mitochondrial-enriched muscle fractions following FI (37-fold, p=0.017); however, autophagy flux, assessed by LC3II accumulation with the lysosomal inhibitor chloroquine, was insignificant suggesting a physiological bottleneck in the clearance of dysfunctional organelles following FI. Ulk1 musclespecific knockout (Ulk1 MKO) mice were used to determine if autophagy is necessary for the recovery of mitochondrial function after muscle damage. Ulk1 MKO mice were weaker (-12%, p=0.012) and demonstrated altered satellite cell dynamics (e.g., proliferation) during muscle regeneration after FI compared to littermate control mice, but determination of autophagy necessity for the recovery of mitochondrial function was inconclusive. This study concludes that autophagy is a tunable cellular response to muscle damaging stress and may influence muscle fiber regeneration through interaction with satellite cells.
Journal of Molecular Medicine, 2014
Metabolic homeostasis is essential for cellular survival and proper tissue function. Multi-systemic metabolic regulation is therefore vital for good health. A number of tissues have the task of maintaining appropriate metabolism, and skeletal muscle is the most abundant of them. Muscle possesses a remarkable plasticity and is able to rapidly adapt to changes in energetic demands by fine-tuning the balance between catabolic and anabolic processes. Autophagy is a catabolic process responsible for the degradation of protein aggregates and damaged organelles, through the autophagosome-lysosome system. Proper regulation of autophagy flux is fundamental for organism homeostasis under physiological conditions and even more in response to metabolic stress, such as during physical activity and nutritional deficits. Both deficient and excessive autophagy are harmful for health and have devastating consequences in a myriad of pathologies. The regulation of autophagy flux in various tissues, and in particular in skeletal muscle, is of great importance for health and tissue homeostasis and represents a feasible mechanism by which physical exercise exerts its beneficial effects on muscle and whole body metabolism. This review is focused on the key molecular mechanisms regulating macromolecule and organelle turnover in muscle during alterations in nutrient availability and energetic demands, as well as their involvement in disease pathogenesis.
Exercise prevents impaired autophagy and proteostasis in a model of neurogenic myopathy
Scientific reports, 2018
Increased proteolytic activity has been widely associated with skeletal muscle atrophy. However, elevated proteolysis is also critical for the maintenance of cellular homeostasis by disposing cytotoxic proteins and non-functioning organelles. We recently demonstrated that exercise activates autophagy and re-establishes proteostasis in cardiac diseases. Here, we characterized the impact of exercise on skeletal muscle autophagy and proteostasis in a model of neurogenic myopathy induced by sciatic nerve constriction in rats. Neurogenic myopathy, characterized by progressive atrophy and impaired contractility, was paralleled by accumulation of autophagy-related markers and loss of acute responsiveness to both colchicine and chloroquine. These changes were correlated with elevated levels of damaged proteins, chaperones and pro-apoptotic markers compared to control animals. Sustained autophagy inhibition using chloroquine in rats (50 mg.kg.day) or muscle-specific deletion of Atg7 in mice ...
Journal of sports science & medicine, 2019
Exercise-induced skeletal muscle adaptation requires degradation of cellular components carried out by autophagy. However, the alteration of autophagy by different intensity of exercise in skeletal muscle is still unknown. In the present study, we investigate whether low, moderate, and high-intensity exercises have different impacts on autophagy gene expression in gastrocnemius and soleus muscles of wistar rats. This work is limited because only rats are used, and does not cover human tissues. Twenty male wistar rats were assigned to four groups: sedentary control, low-intensity (LI, 10 m/minute), moderate-intensity (MI, 20 m/minute), and high-intensity (HI, 30 m/minute) exercises. Training was conducted 30 minutes/day with a 5 times/week interval for 8 weeks. RNA and protein were extracted from gastrocnemius and soleus muscles then stored in -80°C. Specific primers and antibodies for autophagy genes and protein levels were utilized for semi-quantitative PCR and Western Blot. Exerci...
The Journal of physiology, 2015
Studies in rodent muscle suggest that autophagy is regulated by acute exercise, exercise training and insulin stimulation. However, little is known about the regulation of autophagy in human skeletal muscle. Here we investigate the autophagic response to acute one-legged exercise, one-legged exercise training as well as in response to subsequent insulin stimulation in exercised and non-exercised human muscle. Acute one-legged exercise decreased (p<0.01) lipidation of LC3 (∼50 %) and the LC3-II/LC3-I ratio (∼60 %) indicating that content of autophagosomes decreases with exercise in human muscle. The decrease in LC3-II/LC3-I ratio did not correlate with activation of AMPK trimer complexes in human muscle. Consistently, pharmacological AMPK activation with AICAR in mouse muscle did not affect the LC3-II/LC3-I ratio. Four hours after exercise, insulin further reduced (p<0.01) the LC3-II/LC3-I ratio (∼80%) in muscle of the exercised and non-exercised leg in man. This coincided with...