Insulin-like growth factors (IGFs) are essential for local skeletal muscle growth and organismal physiology, but these actions are entwined with glucose homeostasis through convergence with insulin signaling. The objective of this work was to determine whether the effects of IGF-I on growth and metabolism could be separated. We generated muscle-specific IGF-I-deficient (MID) mice that afford inducible deletion of Igf1 at any age. After Igf1 deletion at birth or in young adult mice, evaluations of muscle physiology and glucose homeostasis were performed up to 16 wk of age. MID mice generated at birth had lower muscle and circulating IGF-I, decreased muscle and body mass, and impaired muscle force production. Eight-wk-old male MID had heightened insulin levels with trends of elevated fasting glucose. This phenotype progressed to impaired glucose handling and increased fat deposition without significant muscle mass loss at 16 wk of age. The same phenotype emerged in 16-wk-old MID mice induced at 12 wk of age, compounded with heightened muscle fatigability and exercise intolerance. We assert that muscle IGF-I independently modulates anabolism and metabolism in an age-dependent manner, thus positioning muscle IGF-I maintenance to be critical for both muscle growth and metabolic homeostasis.-Vassilakos, G., Lei, H., Yang, Y., Puglise, J., Matheny, M., Durzynska, J., Ozery, M., Bennett, K., Spradlin, R., Bonanno, H., Park, S., Ahima, R. S., Barton, E. R. Deletion of muscle Igf-I transiently impairs growth and progressively disrupts glucose homeostasis in male mice.

The insulin‐like growth factor (IGF) pathway is essential for promoting growth and survival of virtually all tissues. It bears high homology to its related protein insulin, and as such, there is an interplay between these molecules with regard to their anabolic and metabolic functions. Skeletal muscle produces a significant proportion of IGF‐1, and is highly responsive to its actions, including increased muscle mass and improved regenerative capacity. In this overview, the regulation of IGF‐1 production, stability, and activity in skeletal muscle will be described. Second, the physiological significance of the forms of IGF‐1 produced will be discussed. Last, the interaction of IGF‐1 with other pathways will be addressed. © 2019 American Physiological Society. Compr Physiol 9:413‐438, 2019.

Introduction Dysferlin loss‐of‐function mutations cause muscular dystrophy, accompanied by impaired membrane repair and muscle weakness. Growth promoting strategies including insulin‐like growth factor 1 (IGF‐1) could provide benefit but may cause strength loss or be ineffective. The objective of this study was to determine whether locally increased IGF‐1 promotes functional muscle hypertrophy in dysferlin‐null (Dysf−/−) mice. Methods Muscle‐specific transgenic expression and postnatal viral delivery of Igf1 were used in Dysf−/− and control mice. Increased IGF‐1 levels were confirmed by enzyme‐linked immunosorbent assay. Testing for skeletal muscle mass and function was performed in male and female mice. Results Muscle hypertrophy occurred in response to increased IGF‐1 in mice with and without dysferlin. Male mice showed a more robust response compared with females. Increased IGF‐1 did not cause loss of force per cross‐sectional area in Dysf−/− muscles. Discussion We conclude that increased local IGF‐1 promotes functional hypertrophy when dysferlin is absent and reestablishes IGF‐1 as a potential therapeutic for dysferlinopathies.

Muscle atrophy occurs as a result of prolonged periods of reduced mechanical stimulation associated with injury or disease. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and load sensing pathways can both aid in recovery from disuse through their shared downstream signaling, but their relative contributions to these processes are not fully understood. The goal of this study was to determine if reduced muscle IGF-1 altered the response to disuse and reloading. Adult male mice with inducible muscle-specific IGF-1 deletion (MID) induced 1 week before suspension and age-matched controls (CON) were subjected to hindlimb suspension and reloading. Analysis of muscle force, morphology, gene expression, signaling, and tissue weights were performed in non-suspended mice, and those suspended for 7 days, or reloaded following suspension for 3-, 7-, and 14 days. MID mice displayed diminished IGF-1 protein levels and muscle atrophy prior to suspension. Muscles from suspended CON mice displayed a similar extent of atrophy and depletion of IGF-1, yet combined loss of load and IGF-1 was not additive with respect to muscle mass. In contrast, soleus force generation capacity was diminished to the greatest extent when both suspension and IGF-1 deletion occurred. Recovery of mass, force, and gene expression patterns following suspension were similar in CON and MID mice, even though IGF-1 levels increased only in muscles from CON mice. Diminished strength in disuse atrophy is exacerbated with the loss of muscle IGF-1 production, whereas recovery of mass and strength upon reloading can occur even IGF-1 is low.

PurposeInsulin‐like growth factor‐I (IGF‐I) is an important coordinator of muscle growth, repair, and functional capacity while disuse‐induced skeletal muscle atrophy is a consequence of many diseases and injuries that require prolonged rest. It is known that a lack of muscle activity results in loss of skeletal muscle mass and force generating capacity but it is unclear if locally produced IGF‐I is necessary for recovery from disuse.MethodsMice with muscle‐specific inducible deletion of IGF‐I (MID) and age‐matched controls (CON) underwent hindlimb suspension (HLS) and reloading. Deletion was achieved by the addition of 2mg/mL doxycycline hyclate with 5% sucrose to the mice's drinking water prior to suspension and maintained throughout the course of the experiment. Mice were either left non‐suspended (NS) or suspended for 7 days (SUS) and reloaded for 3 days (Re3), 7 days (Re7), and 14 days (Re14). EDL and soleus muscle function were assessed at each timepoint and tissues were harvested to assess extent of Igf1 deletion, as well as changes in mass, gene expression (qPCR), and IGF‐I content (ELISA). All groups were compared to NS CON mice.ResultsThroughout the duration of the experiment, neither MID or CON mice's body weight changed significantly. During suspension, CON mice exhibited a 20% reduction in soleus mass and no changes for the EDL when normalized to body weight. No normalized mass changes in either muscle were seen in the MID group following suspension. Force generating capacity in CON mice was unaffected by suspension/reloading, while MID mice had a 20 and 23% reduction in specific force for the EDL and soleus, respectively, in SUS and Re7 mice. CON mice showed a reduction of muscle IGF‐I content upon suspension, a marked increase at Re7, and a return to baseline values by Re14. MID mice showed a trend for lower initial IGF‐I levels and remained reduced throughout the course of the experiment. Fiber type distribution and cross‐sectional area did not seem to be significantly affected by Igf1 deletion or suspension/reloading. Fbxo40, Musa1, and Smart expression were unchanged while endogenous Igf1 expression was significantly lower at Re7 in the MID mice compared to CON.ConclusionsWe conclude that a local source of IGF‐I is necessary for muscle recovery from disuse.Support or Funding InformationThis study was supported in part by U54 AR052646This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.