Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

Abstract

The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and ageassociated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal musclespecific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca 2+ through SERCA2.Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan.These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.Skeletal muscle is the major site of postprandial glucose disposal and the primary determinant of resting energy expenditure in mammals [18,19]. Constitutive activation of mTORC1, via musclespecific deletion of its negative regulator Tsc1, results in age-related myoatrophy, dysregulation of autophagy induction and increased expression of mitochondrial enzymes [6,20,21]. Consistent with the latter, cell culture models implicate mTORC1 as a positive regulator of mitochondrial biogenesis and aerobic ATP production [22][23][24]. During the aging process, skeletal muscle exhibits a fiber-type transformation towards a more oxidative phenotype, concomitant with increased mTORC1 activity. In line with these observations, several studies have implicated mTORC1 inhibition as a mechanism of organismal lifespan extension in yeast, worms and mammals [25][26][27]; however, the tissue or tissues that link mTORC1 activity to lifespan have not yet been identified.Skeletal muscle is an important tissue for understanding aging, insulin sensitivity and changes in energy metabolism, as functional differences in muscle strength predict lifespan in humans [28][29][30][31][32][33].Furthermore, mTORC1 regulates several important metabolic processes in muscle; including oxidative stress, the unfolded protein response, autophagy and lipid metabolism [20,34,35]. Here, we have performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. We show that chronic mTORC1 activation in skeletal muscle (...

Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice

“…Reduced mTORC1 signaling in skeletal muscle delays sarcopenia and improves markers of muscle health 84 , and skeletal muscle mTORC1 signaling regulates lifespan 87 . There are some similarities between the effects of a Low BCAA diet and the effects of rapamycin, including a decrease in cancer and a trend towards improvements in cardiovascular parameters, including ejection fraction and fractional shortening 88 , 89 .…”

Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance

“…mTORC1 signaling in the skeletal muscle is a major regulator of whole-body metabolism, as either its inhibition or activation causes leanness and resistance to obesity through distinct mechanisms [ 29 ]. Recently, it was proposed that mTORC1 activity coordinately regulates the expression of many genes to promote muscle EE and reduce body mass in mice fed a HFD [ 32 ]. Supporting this conclusion, RNAseq comparing gene expression in muscle of Cntr, LDKO and LDKO · Fst L/L mice revealed elevated levels of several amino acid transporters in LDKO muscle—including significantly higher Slc6a19 (neutral aa transporter) and Slc6a17 (Leu, Pro, Ala, Gly transporter), or an upward trend of many others—each of which decreased toward normal in LDKO · Fst L/L muscle ( Figure 7 F).…”

“…Expression of fatty acid transporters (Fabp3, Slc27a1) also increased in LDKO muscle versus Cntr or LDKO · Fst L/L muscle ( Figure 7 F). Strikingly, several genes that promote muscle EE through their involvement in futile or uncoupled Ca 2+ cycling were expressed at higher levels specifically in LDKO muscle—including genes encoding the Serca2 ATPase (Sarcoplasmic/Endoplasmic Reticulum Ca 2+ -transporting 2), Ca 2+ binding protein Casq2 (Calsequestrin 2), and Sln (Sarcolipin) that uncouples ATP hydrolysis from Ca 2+ -transport ( Figure 7 F) [ 32 , 67 ]. Transcripts associated with an increase in muscle oxidative fibers also increased specifically in LDKO muscle—including Tnni1, Myh7, Myh1 and Mb ( Figure 7 F) [ 32 ].…”

“…Strikingly, several genes that promote muscle EE through their involvement in futile or uncoupled Ca 2+ cycling were expressed at higher levels specifically in LDKO muscle—including genes encoding the Serca2 ATPase (Sarcoplasmic/Endoplasmic Reticulum Ca 2+ -transporting 2), Ca 2+ binding protein Casq2 (Calsequestrin 2), and Sln (Sarcolipin) that uncouples ATP hydrolysis from Ca 2+ -transport ( Figure 7 F) [ 32 , 67 ]. Transcripts associated with an increase in muscle oxidative fibers also increased specifically in LDKO muscle—including Tnni1, Myh7, Myh1 and Mb ( Figure 7 F) [ 32 ]. Consistent with these changes, palmitate oxidation by isolated muscle mitochondria from LDKO mice fed the HFD 45% was significantly higher than by Cntr or LDKO · Fst L/L mitochondria ( Figure 7 G).…”

“…The Akt→mTORC1 (mechanistic target of rapamycin complex 1) cascade stimulates anabolic pathways in all tissues, including Srebp1c (Sterol regulatory element-binding factor 1)-promoted DNL in the liver [ [22] , [23] , [24] , [25] , [26] ]. In muscle, mTORC1 inhibits autophagy while promoting muscle fiber growth and increasing energy expenditure [ 9 , [27] , [28] , [29] , [30] , [31] , [32] ].…”