Deletion of muscle IGF‐I transiently impairs growth and progressively disrupts glucose homeostasis in male mice

Vassilakos, Georgios; Lei, Hanqin; Yang, Yun Kai; Puglise, Jason M.; Matheny, Michael; Durzyńska, Julia; Ozery, Matan; Bennett, Katherine; Spradlin, Ray A.; Bonanno, Heather; Park, Soo-Hyun; Ahima, Rexford S.; Barton, Elisabeth R.

doi:10.1096/fj.201800459r

Cited by 31 publications

(40 citation statements)

References 62 publications

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“…Muscle function. In vitro muscle function was assessed in the soleus and EDL at the University of Florida Myology Institute Physiological Assessment Core as previously described (28,31). Briefly, soleus and EDL muscles were removed after surgical sedation with ketamine and xylazine and placed in a bath of oxygenated Ringers solution (120 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl 2, 1.2 mM KH2PO4, 1.2 mM MgSO4, 25 mM HEPES, and 5.5 mM glucose).…”

Section: Methodsmentioning

confidence: 99%

Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice

Spaulding

Quindry

Hammer

et al. 2019

Journal of Applied Physiology

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Progressive muscle injury and weakness are hallmarks of Duchenne muscular dystrophy. We showed previously that quercetin (Q) partially protected dystrophic limb muscles from disease-related injury. As quercetin activates PGC-1α through Sirtuin-1, an NAD+-dependent deacetylase, the depleted NAD+ in dystrophic skeletal muscle may limit quercetin efficacy; hence, supplementation with the NAD+ donor, nicotinamide riboside (NR), may facilitate quercetin efficacy. Lisinopril (Lis) protects skeletal muscle and improves cardiac function in dystrophin-deficient mice; therefore, it was included in this study to evaluate the effects of lisinopril used with quercetin and NR. Our purpose was to determine the extent to which Q, NR, and Lis decreased dystrophic injury. We hypothesized that Q, NR, or Lis alone would improve muscle function and decrease histological injury and when used in combination would have additive effects. Muscle function of 11-mo-old DBA (healthy), D2-mdx (dystrophin-deficient), and D2-mdx mice was assessed after treatment with Q, NR, and/or Lis for 7 mo. To mimic typical pharmacology of patients with Duchenne muscular dystrophy, a group was treated with prednisolone (Pred) in combination with Q, NR, and Lis. At 11 mo of age, dystrophin deficiency decreased specific tension and tetanic force in the soleus and extensor digitorum longus muscles and was not corrected by any treatment. Dystrophic muscle was more sensitive to contraction-induced injury, which was partially offset in the QNRLisPred group, whereas fatigue was similar between all groups. Treatments did not decrease histological damage. These data suggest that treatment with Q, NR, Lis, and Pred failed to adequately maintain dystrophic limb muscle function or decrease histological damage. NEW & NOTEWORTHY Despite a compelling rationale and previous evidence to the contrary in short-term investigations, quercetin, nicotinamide riboside, or Lisinopril, alone or in combination, failed to restore muscle function or decrease histological injury in dystrophic limb muscle from D2-mdx mice after long-term administration. Importantly, we also found that in the D2-mdx model, an emerging and relatively understudied model of Duchenne muscular dystrophy dystrophin deficiency caused profound muscle dysfunction and histopathology in skeletal muscle.

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Section: Methodsmentioning

confidence: 99%

Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice

Spaulding

Quindry

Hammer

et al. 2019

Journal of Applied Physiology

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“…IGF1 is typically bound to an IGFBP carrier protein, and upon proteolytic degradation of the IGFBP, IGF1 is liberated and can interact with its receptor, IGF1R, which is a member of the receptor tyrosine kinase (RTK) family of transmembrane receptors (10). IGF1 is a potent activator of skeletal muscle cell proliferation and protein synthesis, and the deletion of IGF1 in muscle fibers results in fiber atrophy and disrupted metabolism (9,11). In bone, overexpression of IGF1 results in increased bone mineral density, and the inactivation of IGF1R in osteoblasts impairs matrix mineralization (12).…”

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confidence: 99%

Insulin‐like growth factor 1 signaling in tenocytes is required for adult tendon growth

et al. 2019

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Tenocytes serve to synthesize and maintain collagen fibrils and other extracellular matrix proteins in tendon. Despite the high prevalence of tendon injury, the underlying biologic mechanisms of postnatal tendon growth and repair are not well understood. IGF1 plays an important role in the growth and remodeling of numerous tissues but less is known about IGF1 in tendon. We hypothesized that IGF1 signaling is required for proper tendon growth in response to mechanical loading through regulation of collagen synthesis and cell proliferation. To test this hypothesis, we conditionally deleted the IGF1 receptor (IGF1R) in scleraxis (Scx)‐expressing tenocytes using a tamoxifen‐inducible Cre‐recombinase system and caused tendon growth in adult mice via mechanical overload of the plantaris tendon. Compared with control Scx‐expressing IGF1R‐positive (Scx:IGF1R+) mice, in which IGF1R is present in tenocytes, mice that lacked IGF1R in their tenocytes [Scx‐expressing IGF1R‐negative (Scx:IGF1RΔ) mice] demonstrated reduced cell proliferation and smaller tendons in response to mechanical loading. Additionally, we identified that both the PI3K/protein kinase B and ERK pathways are activated downstream of IGF1 and interact in a coordinated manner to regulate cell proliferation and protein synthesis. These studies indicate that IGF1 signaling is required for proper postnatal tendon growth and support the potential use of IGF1 in the treatment of tendon disorders.—Disser, N. P., Sugg, K. B., Talarek, J. R., Sarver, D. C., Rourke, B. J., Mendias, C. L. Insulin‐like growth factor 1 signaling in tenocytes is required for adult tendon growth. FASEB J. 33, 12680–12695 (2019). http://www.fasebj.org

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“…Second, a more speculative point is that, because increased muscle mass combined with a lack of changed body weight in the male Dysf +/+ : mIgf +/+ mice occurs, it reflects findings in previous studies in which modulating muscle IGF-1 led to sex-specific alterations locally in muscle and globally in fat content. 30,[38][39][40][41] Thus, it is essential to evaluate male and female mice separately for global IGF-1 dependent changes in muscle mass.…”

Section: Discussionmentioning

confidence: 99%

Functional muscle hypertrophy by increased insulin‐like growth factor 1 does not require dysferlin

et al. 2019

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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.

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Deletion of muscle IGF‐I transiently impairs growth and progressively disrupts glucose homeostasis in male mice

Cited by 31 publications

References 62 publications

Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice

Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice

Insulin‐like growth factor 1 signaling in tenocytes is required for adult tendon growth

Functional muscle hypertrophy by increased insulin‐like growth factor 1 does not require dysferlin

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