sirolimus and Sarcopenia

The mammalian target of rapamycin (mTOR) is a major regulator of skeletal myocyte viability. The signaling pathways triggered by mTOR vary according to the type of endogenous and exogenous factors (e.g., redox balance, nutrient availability, physical activity) as well as organismal age. Here, we provide an overview of mTOR signaling in skeletal muscle, with a special focus on the role played by mTOR in the development of sarcopenia. Intervention strategies targeting mTOR in sarcopenia (e.g., supplementation of plant extracts, hormones, inorganic ions, calorie restriction, and exercise) have also been discussed.

Topics: Animals; Humans; Muscle Fibers, Skeletal; Muscle, Skeletal; Sarcopenia; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Human target of rapamycin (TOR) is a kinase that stimulates protein synthesis in the skeletal muscle in response to amino acids and physical activity.. A comprehensive literature search was conducted on the PubMed database from its inception up to May 2021 to retrieve information on the effects of TOR and glucagon on muscle function. Articles written in English regarding human subjects were included.. l-leucine activates TOR to initiate protein synthesis in the skeletal muscle. Glucagon has a crucial role suppressing skeletal muscle protein synthesis by increasing l-leucine oxidation and the irreversible loss of this amino acid. Glucagon-induced l-leucine oxidation suppresses TOR and attenuates the ability of skeletal muscle to synthesize proteins. Conditions associated with increased glucagon secretion typically feature reduced ability to synthesize proteins in the skeletal muscle that may evolve into sarcopenia. Animal protein ingestion, unlike vegetable protein, stimulates glucagon secretion. High intake of animal protein increases l-leucine oxidation and promotes the use of amino acids as fuel. Sarcopenia and arterial stiffness characteristically occur together in conditions featuring insulin resistance, such as aging. Insulin resistance mediates the relationship between aging and sarcopenia and arterial stiffness. The loss of skeletal muscle fibers that characterizes sarcopenia is followed by collagen and lipid accumulation. Likewise, insulin resistance is associated with arterial stiffness and intima-media thickening due to adaptive accretion of collagen and lipids in the arterial wall.. Human TOR participates in the pathogenesis of sarcopenia and arterial stiffness, although its effects remain to be fully elucidated.

Topics: Animals; Glucagon; Humans; Muscle Proteins; Muscle, Skeletal; Sarcopenia; Sirolimus

Caloric restriction and physical exercise have proven beneficial against age-associated changes in body composition and declining physical performance; however, little is known regarding what benefit these interventions might have when initiated late in life. The study of mimetics of diet and exercise and the combination thereof may provide additional treatments for a vulnerable elderly population; however, how and when to initiate such interventions requires consideration in developing the most safe and efficacious treatment strategies. In this review, we focus on preclinical late-life intervention studies, which assess the relationship between physical function, sarcopenia, and body composition. We provide a conceptual framework for the ever-changing definition of sarcopenia and a rationale for the use of an appropriate rodent model of this condition. We finish by providing our perspective regarding the implications of this body of work and future areas of research that may also contribute to the ultimate goal of extending healthspan.

Topics: Animals; Body Composition; Caloric Restriction; Enalapril; Exercise; Female; Humans; Longevity; Male; Mice; Rats; Sarcopenia; Sirolimus

Aging is a multifactorial process associated with progressive degradation of physiological integrity and function. One of the greatest factors contributing to the deleterious effects of aging is the decline of functional ability due to loss of muscle mass, strength, and function, a condition termed sarcopenia. Calorie restriction (CR) has consistently been shown to extend lifespan and delay the onset and progression of various age-related diseases, including sarcopenia. Additional anti-aging interventions that are receiving scientific attention are CR mimetics. Of these pharmacological compounds, rapamycin has shown similar CR-related longevity benefits without the need for diet restrictions. To investigate the potential role of rapamycin as an anti-sarcopenic alternative to CR, we conducted a study in male and female C57BL/6 J mice to assess the effects of rapamycin on age-related gene expression changes in skeletal muscle associated with loss of muscle mass, strength, and function, relative to control. We hypothesize that the effects of rapamycin will closely align with CR with respect to physical function and molecular indices associated with muscle quality. Our results indicate CR and rapamycin provide partial protection against age-related decline in muscle, while engaging uniquely different molecular pathways in skeletal muscle. Our preclinical findings of the therapeutic potential of rapamycin or a CR regimen on geroprotective benefits in muscle should be extended to translational studies towards the development of effective strategies for the prevention and management of sarcopenia.

Topics: Animals; Caloric Restriction; Female; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Sarcopenia; Sirolimus

Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mammalian target of rapamycin (mTOR) signalling. We wanted to elucidate the functional role of mTOR in muscle contractility. Most loss-of-function studies for mTOR signalling have used the drug rapamycin to inhibit some of the signalling downstream of mTOR. However, given that rapamycin does not inhibit all mTOR signalling completely, we generated a double knockout for mTOR and for the scaffold protein of mTORC1, raptor, in skeletal muscle. We found that double knockout in mice results in a more severe phenotype compared with deletion of raptor or mTOR alone. Indeed, these animals display muscle weakness, increased fibre denervation and a slower muscle relaxation following tetanic stimulation. This is accompanied by a shift towards slow-twitch fibres and changes in the expression levels of calcium-related genes, such as Serca1 and Casq1. Double knockout mice show a decrease in calcium decay kinetics after tetanus in vivo, suggestive of a reduced calcium reuptake. In addition, RNA sequencing analysis revealed that many downregulated genes, such as Tcap and Fhod3, are linked to sarcomere organization. These results suggest a key role for mTOR signalling in maintaining proper fibre relaxation in skeletal muscle. KEY POINTS: Skeletal muscle wasting and weakness have been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and are accompanied by altered mammalian target of rapamycin (mTOR) signalling. Mammalian target of rapamycin plays a crucial role in the maintenance of muscle mass and functionality. We found that the loss of both mTOR and raptor results in contractile abnormalities, with severe muscle weakness and delayed relaxation following tetanic stimulation. These results are associated with alterations in the expression of genes involved in sarcomere organization and calcium handling and with an impairment in calcium reuptake after contraction. Taken together, these results provide a mechanistic insight into the role of mTOR in muscle contractility.

Topics: Animals; Calcium; Gene Deletion; Mice; Mice, Knockout; Muscle Weakness; Muscle, Skeletal; Regulatory-Associated Protein of mTOR; Sarcopenia; Sirolimus; TOR Serine-Threonine Kinases

With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.

Topics: Aging; Animals; Cell Line; Disease Models, Animal; Electromyography; Gene Expression Regulation; Humans; Laser Capture Microdissection; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Muscle Fibers, Skeletal; Myoblasts; Neuromuscular Junction; Patch-Clamp Techniques; RNA-Seq; Sarcopenia; Signal Transduction; Sirolimus

Topics: Aging; Animals; Muscle, Skeletal; Protective Agents; Sarcopenia; Sirolimus

Loss of skeletal muscle mass and force aggravates age-related sarcopenia and numerous pathologies, such as cancer and diabetes. The AKT-mTORC1 pathway plays a major role in stimulating adult muscle growth; however, the functional role of its downstream mediators in vivo is unknown. Here, we show that simultaneous inhibition of mTOR signaling to both S6K1 and 4E-BP1 is sufficient to reduce AKT-induced muscle growth and render it insensitive to the mTORC1-inhibitor rapamycin. Surprisingly, lack of mTOR signaling to 4E-BP1 only, or deletion of S6K1 alone, is not sufficient to reduce muscle hypertrophy or alter its sensitivity to rapamycin. However, we report that, while not required for muscle growth, S6K1 is essential for maintaining muscle structure and force production. Hypertrophy in the absence of S6K1 is characterized by compromised ribosome biogenesis and the formation of p62-positive protein aggregates. These findings identify S6K1 as a crucial player for maintaining muscle function during hypertrophy.

Topics: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Cell Cycle Proteins; Eukaryotic Initiation Factors; Humans; Hypertrophy; Mice; Mice, Knockout; Muscle, Skeletal; Oncogene Protein v-akt; Peptides; Phosphoproteins; Phosphorylation; Protein Aggregates; Ribosomal Protein S6 Kinases, 70-kDa; Ribosomes; Sarcopenia; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Aging is regulated by conserved signaling pathways. The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases regulates several of these pathways, but the role of GSK-3 in aging is unknown. Herein, we demonstrate premature death and acceleration of age-related pathologies in the Gsk3a global KO mouse. KO mice developed cardiac hypertrophy and contractile dysfunction as well as sarcomere disruption and striking sarcopenia in cardiac and skeletal muscle, a classical finding in aging. We also observed severe vacuolar degeneration of myofibers and large tubular aggregates in skeletal muscle, consistent with impaired clearance of insoluble cellular debris. Other organ systems, including gut, liver, and the skeletal system, also demonstrated age-related pathologies. Mechanistically, we found marked activation of mTORC1 and associated suppression of autophagy markers in KO mice. Loss of GSK-3α, either by pharmacologic inhibition or Gsk3a gene deletion, suppressed autophagy in fibroblasts. mTOR inhibition rescued this effect and reversed the established pathologies in the striated muscle of the KO mouse. Thus, GSK-3α is a critical regulator of mTORC1, autophagy, and aging. In its absence, aging/senescence is accelerated in multiple tissues. Strategies to maintain GSK-3α activity and/or inhibit mTOR in the elderly could retard the appearance of age-related pathologies.

Topics: Aging; Animals; Autophagy; Bone and Bones; Cardiovascular Diseases; Cellular Senescence; Everolimus; Glycogen Synthase Kinase 3; Hepatocytes; Indoles; Kaplan-Meier Estimate; Knee Joint; Liver; Maleimides; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes; Muscle, Skeletal; Myocardium; Phenotype; Proteins; Sarcopenia; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sarcopenia is the loss of muscle mass and strength which occurs with aging. Whether the molecular basis of sarcopenia differs with muscle type and across sex is not well understood. Here we examine how aging affects the regulation of protein kinase B (Akt), the mammalian target of rapamycin (mTOR), AMP activated kinase (AMPK), p70 ribosomal S6 kinase (p70s6k), S6 ribosomal protein (rps6) and calcineurin (CaN) in the slow soleus and fast extensor digitorum longus (EDL) muscles of 6- (adult), 30- (aged), and 36-month (very aged) male and 6- (adult), 26- (aged), and 30-month (very aged) female Fischer 344xBrown Norway (F344BN) rats. In male animals, soleus and EDL muscle to body weight ratios decreased steadily with age while in the females, losses remained unchanged after 26 months. These age-related changes in the degree of muscle atrophy across sex were associated with differences in the regulation of Akt, mTOR, and p70s6k in the slow-twitch soleus and the regulation of AMPK, 4EBP1, p70s6k and rpS6 in the fast-twitch EDL. Irrespective of muscle type, aging in both the genders was associated with increased calcineurin expression. Taken together, these data suggest that indices of protein synthesis and muscle adaptation are regulated differently with aging in different muscle types and sex.

Topics: Aging; Animals; Calcineurin; Female; Male; Mammals; Muscle, Skeletal; Muscular Atrophy; Muscular Diseases; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred BN; Rats, Inbred F344; Ribosomal Protein S6 Kinases, 70-kDa; Sarcopenia; Signal Transduction; Sirolimus