Partial Inhibition of mTORC1 in Aged Rats Counteracts the Decline in Muscle Mass and Reverses Molecular Signaling Associated with Sarcopenia

ABSTRACT There is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established positive modulator of muscle mass, to be surprisingly hyperactivated in sarcopenic muscle. Furthermore, partial inhibition of the mTORC1 pathway counteracted sarcopenia, as determined by observing an increase in muscle mass and fiber type cross-sectional area in select muscle groups, again surprising because mTORC1 signaling has been shown to be required for skeletal muscle mass gains in some models of hypertrophy. Additionally, several genes related to senescence were downregulated and gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a “rapalog” (a pharmacological agent related to rapamycin). Therefore, partial mTORC1 inhibition may delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia.

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Inhibition of mTORC1 signaling in aged rats counteracts the decline in muscle mass and reverses multiple parameters of muscle signaling associated with sarcopenia

10.1101/591891 ◽

2019 ◽

Cited By ~ 1

Author(s):

Giselle A. Joseph ◽

Sharon Wang ◽

Weihua Zhou ◽

Garrett Kimble ◽

Herman Tse ◽

...

Keyword(s):

Muscle Mass ◽

Fiber Type ◽

Mammalian Target Of Rapamycin ◽

Pharmacological Interventions ◽

Cross Sectional ◽

Multiple Parameters ◽

Mtorc1 Signaling ◽

Positive Modulator ◽

Mtorc1 Pathway

AbstractThere is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established critical positive modulator of mass, to be hyperactivated in sarcopenic muscle. Furthermore, inhibition of the mTORC1 pathway counteracted sarcopenia as determined by observing an increase in muscle mass and fiber type cross sectional area, surprising because mTORC1 signaling has been shown to be required for muscle mass gains in some settings. Additionally, several genes related to senescence were downregulated, while gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a rapalog. Therefore mTORC1 inhibition may delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia.

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Hypertrophy and proliferation of skeletal muscle fibers from aged quail

Journal of Applied Physiology ◽

10.1152/jappl.1995.78.1.293 ◽

1995 ◽

Vol 78 (1) ◽

pp. 293-299 ◽

Cited By ~ 26

Author(s):

J. A. Carson ◽

M. Yamaguchi ◽

S. E. Alway

Keyword(s):

Muscle Mass ◽

Fiber Type ◽

Right Wing ◽

Left Wing ◽

Cross Sectional ◽

Anterior Latissimus Dorsi ◽

Fiber Number ◽

Fiber Type Distribution ◽

Distribution Shifts ◽

The Right

The purpose of this study was to determined whether fibers in the anterior latissimus dorsi (ALD) muscle from aged Japanese quail have decreased hypertrophic or proliferative responses to 30 days of stretch overload compared with fibers from adult birds. Two groups of quail were studied, 12-wk-old quail (adult; n = 16) and 90-wk-old quail (aged; n = 16). The left wing of each bird was overloaded with a weight corresponding to 10% of the bird's body weight, and the right wing served as the intra-animal control. Quails were killed after 30 days of stretch overload. Total fiber number was quantified by counting all the fibers in a transverse section from the midbelly of the ALD muscle. ALD muscles in aged quails retained the capacity to increase their muscle mass (145%), total fiber number (49%), and fiber cross-sectional area (54%) in response to stretch overload. The ALD muscle in aged quail had a significantly lower increase in muscle mass (33%) and mass corrected for nonmuscle tissue (36%) compared with the ALD from young adult birds. Age had no effect on fiber type distribution shifts with stretch. These results suggest that although muscles in old birds have a substantial ability to adapt to enlarge, stretch-induced hypertrophy is attenuated in muscles from old quail.

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Modulation of mTORC1 Signaling Pathway by HIV-1

Cells ◽

10.3390/cells9051090 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1090 ◽

Cited By ~ 2

Author(s):

Burkitkan Akbay ◽

Anna Shmakova ◽

Yegor Vassetzky ◽

Svetlana Dokudovskaya

Keyword(s):

Cellular Response ◽

Cellular Proliferation ◽

Mammalian Target Of Rapamycin ◽

Host Cells ◽

Promising Strategy ◽

Mtorc1 Signaling ◽

Mtorc1 Pathway ◽

Recent Trends ◽

Hiv 1

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular proliferation and survival which controls cellular response to different stresses, including viral infection. HIV-1 interferes with the mTORC1 pathway at every stage of infection. At the same time, the host cells rely on the mTORC1 pathway and autophagy to fight against virus replication and transmission. In this review, we will provide the most up-to-date picture of the role of the mTORC1 pathway in the HIV-1 life cycle, latency and HIV-related diseases. We will also provide an overview of recent trends in the targeting of the mTORC1 pathway as a promising strategy for HIV-1 eradication.

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Redox Status and Muscle Pathology in Rheumatoid Arthritis: Insights from Various Rat Hindlimb Muscles

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2484678 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

A. B. Oyenihi ◽

T. Ollewagen ◽

K. H. Myburgh ◽

Y. S. L. Powrie ◽

C. Smith

Keyword(s):

Rheumatoid Arthritis ◽

Muscle Mass ◽

Fiber Type ◽

Vastus Lateralis ◽

Redox Status ◽

Current Data ◽

Muscle Pathology ◽

Sprague Dawley ◽

Cross Sectional ◽

Rheumatoid Cachexia

Due to atrophy, muscle weakness is a common occurrence in rheumatoid arthritis (RA). The majority of human studies are conducted on the vastus lateralis muscle—a muscle with mixed fiber type—but little comparative data between multiple muscles in either rodent or human models are available. The current study therefore assessed both muscle ultrastructure and selected redox indicators across various muscles in a model of collagen-induced rheumatoid arthritis in female Sprague-Dawley rats. Only three muscles, the gastrocnemius, extensor digitorum longus (EDL), and soleus, had lower muscle mass (38%, 27%, and 25% loss of muscle mass, respectively; all at least P<0.01), while the vastus lateralis muscle mass was increased by 35% (P<0.01) in RA animals when compared to non-RA controls. However, all four muscles exhibited signs of deterioration indicative of rheumatoid cachexia. Cross-sectional area was similarly reduced in gastrocnemius, EDL, and soleus (60%, 58%, and 64%, respectively; all P<0.001), but vastus lateralis (22% smaller, P<0.05) was less affected, while collagen deposition was significantly increased in muscles. This pathology was associated with significant increases in tissue levels of reactive oxygen species (ROS) in all muscles except the vastus lateralis, while only the gastrocnemius had significantly increased levels of lipid peroxidation (TBARS) and antioxidant activity (FRAP). Current data illustrates the differential responses of different skeletal muscles of the hindlimb to a chronic inflammatory challenge both in terms of redox changes and resistance to cachexia.

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Atrophy, but not necrosis, in rabbit skeletal muscle denervated for periods up to one year

AJP Cell Physiology ◽

10.1152/ajpcell.00085.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. C440-C451 ◽

Cited By ~ 50

Author(s):

Z. Ashley ◽

H. Sutherland ◽

H. Lanmüller ◽

M. F. Russold ◽

E. Unger ◽

...

Keyword(s):

Skeletal Muscle ◽

Morphological Changes ◽

Fiber Type ◽

Common Peroneal Nerve ◽

Cross Sectional Area ◽

Extensive Literature ◽

Sectional Area ◽

Cross Sectional ◽

Muscle Groups

Our understanding of the effects of long-term denervation on skeletal muscle is heavily influenced by an extensive literature based on the rat. We have studied physiological and morphological changes in an alternative model, the rabbit. In adult rabbits, tibialis anterior muscles were denervated unilaterally by selective section of motor branches of the common peroneal nerve and examined after 10, 36, or 51 wk. Denervation reduced muscle mass and cross-sectional area by 50–60% and tetanic force by 75%, with no apparent reduction in specific force (force per cross-sectional area of muscle fibers). The loss of mass was associated with atrophy of fast fibers and an increase in fibrous and adipose connective tissue; the diameter of slow fibers was preserved. Within fibers, electron microscopy revealed signs of ultrastructural disorganization of sarcomeres and tubular systems. This, rather than the observed transformation of fiber type from IIx to IIa, was probably responsible for the slow contractile speed of the muscles. The muscle groups denervated for 10, 36, or 51 wk showed no significant differences. At no stage was there any evidence of necrosis or regeneration, and the total number of fibers remained constant. These changes are in marked contrast to the necrotic degeneration and progressive decline in mass and force that have previously been found in long-term denervated rat muscles. The rabbit may be a better choice for a model of the effects of denervation in humans, at least up to 1 yr after lesion.

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Deletion of Growth Hormone Receptors in Postnatal Skeletal Muscle of Male Mice Does Not Alter Muscle Mass and Response to Pathological Injury

Endocrinology ◽

10.1210/en.2013-1209 ◽

2013 ◽

Vol 154 (10) ◽

pp. 3776-3783 ◽

Cited By ~ 18

Author(s):

Archana Vijayakumar ◽

Nicholas J. Buffin ◽

Emily J. Gallagher ◽

Jeffrey Blank ◽

Yingjie Wu ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Receptor ◽

Muscle Mass ◽

Hormone Receptors ◽

Fiber Type ◽

Receptor Signaling ◽

Cross Sectional ◽

Adult Mice ◽

Type Composition ◽

Insulin Receptor Signaling

In this study, we investigated whether loss of GH receptor (GHR) signaling in postnatal skeletal muscle alters muscle mass and regenerative ability in adult mice and whether this was dependent on IGF-1 receptor (IGF-1R) signaling. To do so, we used mouse models with skeletal muscle-specific loss of GHR signaling (mGHRKO), IGF-1R and insulin receptor signaling (MKR), or both GHR and IGF-1R/insulin receptor signaling (mGHRKO/MKR). We did not find a reduction in muscle cross-sectional area, fiber type composition, or response to pathological muscle injury in male mGHRKO and mGHRKO/MKR mice when compared with control and MKR mice, respectively. This could potentially be explained by unchanged skeletal muscle Igf-1 expression in mGHRKO and mGHRKO/MKR mice relative to control and MKR mice, respectively. Furthermore, MKR and mGHRKO/MKR mice, but not mGHRKO mice, demonstrated reduced fiber fusion after cardiotoxin injection, suggesting that IGF-1, and not GH, promotes fiber fusion in adult mice. In summary, our data suggest that GHR signaling in postnatal skeletal muscle does not play a significant role in regulating muscle mass or muscle regeneration. Additionally, in our model, muscle Igf-1 expression is not dependent on GHR signaling in postnatal skeletal muscle.

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Abstract 300: The Role of Rheb-mTORC1 Pathway in Cardiac Developmental Growth and Pathological Hypertrophy

Circulation Research ◽

10.1161/res.111.suppl_1.a300 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Takahito Tamai ◽

Tomokazu Murakawa ◽

Osamu Yamaguchi ◽

Shungo Hikoso ◽

Issei Komuro ◽

...

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Cross Sectional Area ◽

Heart Weight ◽

Sectional Area ◽

Cross Sectional ◽

Pathological Hypertrophy ◽

Mtorc1 Signaling ◽

Mtorc1 Pathway

Mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr kinase and plays a key role in cellular growth. Multiprotein complexes called mTOR complex 1 (mTORC1) signaling is essential in cardiac hypertrophy. Many signaling pathways which can regulate mTORC1 activity have been previously reported, however, the regulation of mTORC1 is not fully elucidated. A small GTPase, Rheb (Ras homologue enriched in brain)-GTP activates mTORC1. In this study, to examine the contribution of Rheb in mTORC1 signaling in vivo hearts, we generated floxed Rheb mice to obtain cardiac-specific Rheb-deficient mice. First, to examine the role of Rheb-mTORC1 pathway in developmental cardiac hypertrophy, we generated Rheb-/- mice by crossing Rhebflox/flox mice with alpha MHC-Cre transgenic mice. Rheb-/- were born in Mendelian ratio. Echocardiographic analysis revealed that chamber dimension and contractile function of Rheb-/- were similar compared to those of control mice (Rheb+/+) 5 days after birth. However, all of them died between 8 and 10 days after birth due to cardiac dysfunction and heart failure. Rheb-/- exhibited cardiac dilatation and reduced contractility 8 days after birth. The heart weight to body weight ratio and the cross-sectional area of cardiomyocytes were significantly lower in Rheb-/- 8 days after birth. Next, to examine the role of Rheb-mTORC1 pathway in pathological hypertrophy, we generated conditional Rheb-/- mice by crossing Rhebflox/flox mice with Mer-Cre-Mer transgenic mice. Cardiac pressure overload was induced by means of transverse aortic constriction (TAC), and mice were sacrificed one week after TAC. The heart weight to tibia length ratio and the cross-sectional area of cardiomyocytes were significantly increased in both TAC-operated control and conditional Rheb-/- group compared to that of corresponding sham-operated group. Taken together, Rheb is not essential in pathological hypertrophy, but is essentilal in cardiac developmental hypertrophy in the post-neonatal period.

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Neurotrophic factors enhance the survival of muscle fibers in EDL, but not SOL, after neonatal nerve injury

AJP Cell Physiology ◽

10.1152/ajpcell.00081.2002 ◽

2002 ◽

Vol 283 (3) ◽

pp. C950-C959 ◽

Cited By ~ 18

Author(s):

Kambiz Mousavi ◽

Wilson Miranda ◽

David J. Parry

Keyword(s):

Muscle Mass ◽

Motor Neurons ◽

Fiber Type ◽

Muscle Fibers ◽

Muscle Fiber Types ◽

Sciatic Nerve Crush ◽

Fiber Types ◽

Differential Distribution ◽

Nerve Crush ◽

Cross Sectional

Neonatal sciatic nerve crush results in a sustained reduction of the mass of both extensor digitorum longus (EDL) and soleus (SOL) muscles in the rat. Type IIB fibers are selectively lost from EDL. We have investigated the effects of ciliary neurotrophic factor (CNTF) combined with neurotrophin (NT)-3 or NT-4 on muscle mass, as well as the number, cross-sectional area, and distribution of muscle fiber types and the number of motor neurons innervating EDL and SOL 3 mo after transient axotomy 5 days after birth. Both NT treatments prevented the axotomy-induced loss of muscle mass in both EDL and SOL and of total number of muscle fibers in EDL but not in SOL. Although IIB fiber loss was not prevented, both NT treatments resulted in altered fiber type distribution. Both NT combinations also reduced the loss of EDL motor neurons. These data suggest that a differential distribution of NT receptors on either motor neurons or muscle fibers may lead to different levels of susceptibility to neonatal axotomy.

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Influence of brief daily tendon vibration on rat soleus muscle in non-weight-bearing situation

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.1.3 ◽

1999 ◽

Vol 87 (1) ◽

pp. 3-9 ◽

Cited By ~ 51

Author(s):

Maurice Falempin ◽

Soumeya Fodili In-Albon

Keyword(s):

Relaxation Time ◽

Muscle Mass ◽

Soleus Muscle ◽

Fiber Type ◽

Weight Bearing ◽

Hindlimb Unloading ◽

Tendon Vibration ◽

Contraction Time ◽

Constant Frequency ◽

Cross Sectional

The purpose of this study was to investigate whether tendon vibration could prevent soleus muscle atrophy during hindlimb unloading (HU). Mechanical vibrations with a constant low amplitude (0.3 mm) were applied (192 s/day) with constant frequency (120 Hz) to the Achilles tendon of the unloaded muscle during the 14-day HU period. Significant reductions in muscle mass (−41%), fiber size, maximal twitch (−54%), and tetanic tensions (−73%) as well as changes in fiber type and electrophoretic profiles and twitch-time parameters (−31% in the contraction time and −30% in the half relaxation time) were found after 14 days of HU when compared with the control soleus. Tendon vibration applied during HU significantly attenuated, but did not prevent, 1) the loss of muscle mass (17 vs. 41%); 2) the decrease in the fiber cross-sectional area of type IIA (−28 vs. −50%) and type IIC (−29 vs. −56%) fibers; and 3) the decrease in maximal twitch (−3 vs. −54%) and maximal tetanic tensions (−29 vs. −73%) and the half relaxation time (1 vs. −30%). Changes in the contraction time and in histological and electrophoretical parameters associated with HU were not counteracted. These findings suggest that tendon vibration can be used as a paradigm to counteract the atrophic process observed after HU.

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Mechanical properties of the latissimus dorsi muscle after cyclic training

Journal of Applied Physiology ◽

10.1152/japplphysiol.00218.2002 ◽

2002 ◽

Vol 93 (2) ◽

pp. 649-659 ◽

Cited By ~ 3

Author(s):

Graham N. Askew ◽

Valerie M. Cox ◽

John D. Altringham ◽

David F. Goldspink

Keyword(s):

Muscle Mass ◽

Fatigue Resistance ◽

Power Output ◽

Latissimus Dorsi ◽

Fiber Type ◽

Cross Sectional ◽

Cardiac Assist ◽

Fiber Damage ◽

Cardiac Assist Device ◽

Type Composition

Cardiomyoplasty is a procedure developed to improve heart performance in patients suffering from congestive heart failure. The latissimus dorsi (LD) muscle is surgically wrapped around the failing ventricles and stimulated to contract in synchrony with the heart. The LD muscle is easily fatigued and as a result is unsuitable for cardiomyoplasty. For useful operation as a cardiac-assist device, the fatigue resistance of the LD muscle must be improved while retaining a high power output. The LD muscle of rabbits was subjected to a training regime in which cyclic work was performed. Training transformed the fiber-type composition from approximately equal proportions of fast oxidative glycolytic (FOG) and fast glycolytic (FG) fibers to one composed of almost entirely of FOG with no FG, which increased fatigue resistance while retaining rapid contraction kinetics. Muscle mass and cross-sectional area increased but power output decreased, relative to control muscles. This training regime represents a significant improvement in terms of preserving muscle mass and power compared with other training regimes, while enhancing fatigue resistance, although some fiber damage occurred. The power output of the trained LD muscle was calculated to be sufficient to deliver a significant level of assistance to a failing heart during cardiomyoplasty.

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