Skeletal muscle mass and function are regulated by motor innervation, and denervation results in muscle atrophy. The activity of mammalian target of rapamycin complex 1 (mTORC1) is substantially increased in denervated muscle, but its regulatory role in denervation-induced atrophy remains unclear. At early stages after denervation of skeletal muscle, a pathway involving class II histone deacetylases and the transcription factor myogenin mediates denervation-induced muscle atrophy. We found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of mTORC1 with rapamycin. Activation of mTORC1 through genetic deletion of its inhibitor TSC1 (tuberous sclerosis complex 1) sensitized mice to denervation-induced muscle atrophy and suppressed the kinase activity of Akt, leading to activation of FoxO transcription factors and increasing the expression of genes encoding E3 ubiquitin ligases atrogin [also known as MAFbx (muscle atrophy F-box protein)] and MuRF1 (muscle-specific ring finger 1). Rapamycin treatment of mice restored Akt activity, suggesting that the denervation-induced increase in mTORC1 activity was producing feedback inhibition of Akt. Genetic deletion of the three FoxO isoforms in skeletal muscle induced muscle hypertrophy and abolished the late-stage induction of E3 ubiquitin ligases after denervation, thereby preventing denervation-induced atrophy. These data revealed that mTORC1, which is generally considered to be an important component of anabolism, is central to muscle catabolism and atrophy after denervation. This mTORC1-FoxO axis represents a potential therapeutic target in neurogenic muscle atrophy.

The Midcontinent rift system is a 1.1‐b.y.‐old structure extending from Kansas, through the Lake Superior region, and into southern Michigan. The rift is filled with thick sequences of basaltic volcanic rocks and clastic sediments. For most of its extent it is buried beneath Paleozoic rocks but can be traced by its strong gravity and magnetic anomalies. The rocks of the rift system are exposed only in the Lake Superior region and comprise the Keweenawan Supergroup. Much of the geology of the Keweenawan is beneath Lake Superior and has only been inferred from potential field studies and seismic refraction studies and extrapolation from on‐shore geology. Seismic reflection surveys by the Great Lakes International Multidisciplinary Program on Crustal Evolution in 1986 imaged much of the deep structure of the rift beneath the lake in detail. The reflection profiles across the rift reveal a deep, asymmetrical central graben whose existence and magnitude was not previously documented. They show that, in addition to crustal sagging documented by previous investigations, normal faulting played a major role in subsidence of the axial region of the rift. A sequence of volcanic and sedimentary rocks, in places greater than 30 km thick, fills the graben. Thinner volcanic and sedimentary units lie on broad flanks of the rift outside of the graben. Near the axis, the prerift crust is thinned to about one fourth of its original thickness, apparently by a combination of low‐angle extensional faulting and ductile stretching or distributed shear. The sense of asymmetry of the central graben changes along the trend of the rift, documenting the segmented nature of the structure and suggesting the existence of accommodation zones between the segments. The location of the accommodation zones is inferred from abrupt disruptions in the Bouguer gravity signature of the rift. Uplift of the central graben occurred when the original graben‐bounding normal faults were reactivated as high‐angle reverse faults with throws of 5 km or more in places. The Midcontinent rift has some striking similarities to some younger passive continental margins. We propose that it preserves a record of nearly complete continental separation which, had it not been arrested, would have created a Middle Proterozoic ocean basin.

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age‐related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age‐related muscle atrophy, and GDF signaling is a proposed mechanism.