Resistance Training in Mice.

1 Title Making Mice Mighty: Recent Advances in Translational Models of
2 Load-Induced Muscle Hypertrophy
3 Authors Kevin A. Murach1,2*, John J. McCarthy1,3, Charlotte A. Peterson1,2,3,

4 Cory M. Dungan1,2
1
6 Affiliations The Center for Muscle Biology, University of Kentucky, Lexington,
7 Kentucky 40536
8
2
9 Department of Physical Therapy, College of Health Sciences,
10 University of Kentucky, Lexington, KY 40536
11
3
12 Department of Physiology, College of Medicine, University of
13 Kentucky, Lexington, KY 40536
14
15
16
17 Running Head Making Mice Mighty
18
19 *Correspondence Kevin A. Murach, PhD

20 900 South Limestone Street
21 Room 445 Wethington Building
22 Lexington, KY 40536
23 E-mail: kmu236@g.uky.edu
24 Phone: (859) 218-0872
25
26
27
28
29
30
Downloaded from journals.physiology.org/journal/jappl at Univ of Exeter Library (144.173.006.094) on July 16, 2020.
Mini Review
31 Abstract
32 The ability to genetically manipulate mice allows for gain- and loss-of-function in vivo,
33 making them an ideal model for elucidating mechanisms of skeletal muscle mass
34 regulation. Combining genetic models with mechanical muscle loading enables
35 identification of specific factors involved in the hypertrophic response as well as the
36 ability to test the requirement of those factors for adaptation, thereby informing
37 performance and therapeutic interventions. Until recently, approaches for inducing
38 mechanically-mediated muscle hypertrophy (i.e. resistance-training analogs) have been
39 limited and considered “non-translatable” to humans. This mini-review outlines recent
40 translational advances in loading-mediated strategies for inducing muscle hypertrophy
41 in mice, and highlights the advantages and disadvantages of each method. The skeletal
42 muscle field is poised for new breakthroughs in understanding mechanisms regulating
43 load-induced muscle growth given the numerous murine tools that have very recently
44 been described.
45
46
47
48
49
50
51
52
53
54
55
Mini Review
56 Introduction
57 Key regulators of muscle mass discovered using genetic or pharmacological gain- and
58 loss-of function approaches in mice are often subsequently shown to be altered by
59 loading in humans (i.e. acute resistance exercise and/or training), likely contributing to
60 muscle hypertrophy (5, 12, 38, 39, 48, 49). The development of murine muscle-specific
61 Cre/Lox and Tet-On technologies over the last decade now allows for unprecedented
62 insight into the modifiable factors affecting muscle growth in vivo (24, 37, 40). Moving
63 beyond association and correlation, the utility of mouse models for mechanistically
64 understanding skeletal muscle mass regulation is inarguable and invaluable (55).
65 To identify targets associated with load-mediated muscle hypertrophy, as well as test

66 the requirement of those targets for growth in vivo, a surgical model of overload in mice
67 has historically been the standard (18, 54). This method, termed synergist ablation,
68 involves the excision of one large muscle or a group of muscles to elicit a compensatory
69 growth response from a smaller muscle through ambulation. Most often, the tibialis
70 anterior (dorsiflexor) or gastrocnemius/soleus complex (plantarflexors) are partially or
71 completely removed to overload the extensor digitorum longus or plantaris, respectively.
72 Employed for almost 50 years in mice (26, 50), synergist ablation induces rapid
73 hypertrophy (<2 weeks) and has been leveraged by our laboratory and others to
74 understand cellular and molecular aspects of acute and chronic mechanically-induced
75 muscle hypertrophy (8, 29, 35, 36, 44, 56, 59). While widely adopted, synergist ablation
76 has distinct drawbacks not limited to its invasiveness, tendency to cause
77 damage/degeneration-regeneration and/or muscle fiber splitting, extreme rate and
78 magnitude of growth, isolated functional and metabolic profiles of the muscles being
79 overloaded, continual and irreversible loading stimulus, and ambiguity with respect to
80 the signal that triggers growth (e.g. stretch versus tension) (1, 27, 42, 54). Although the
81 surgical approach has recently been modified to attenuate muscle damage (16, 44, 60),
82 translational models of skeletal muscle hypertrophy that more closely reflect human
83 resistance training are still necessary to obtain an accurate understanding of load-
84 induced adaptations; this has proved challenging since mice are resistant to operant
85 conditioning for exercise.
Mini Review
86 Very recently, an explosion of alternatives to synergist ablation for enhancing muscle

87 mass through loading have been described for mice. All approaches are comparatively
88 more translatable to human exercise than surgical methods and may have specific
89 clinical implications. Each stimulus is also unique and involves different aspects of load-
90 induced adaptation that could be used in combination to provide a broader view of
91 muscle hypertrophic adaptation. The purpose of this mini-review is to highlight these
92 recent advancements and address the advantages and disadvantages of each method.
93 Our hope is that this information will assist muscle researchers in selecting the optimal
94 loading approach to study muscle hypertrophy, and ultimately facilitate the discovery of
95 genes and therapies that preserve or enhance muscle mass.
96 Progressive Weighted Wheel Running
97 Mice are highly active creatures with an affinity for wheel-running. With respect to
98 muscle hypertrophy, un-weighted wheel running in mice may or may not elicit muscle
99 and/or fiber type-specific hypertrophy (3, 6, 33). In our hands, at least in the plantaris
100 muscle, eight weeks of voluntary wheel running (8-10 km/night) was insufficient to elicit
101 muscle growth in adult (>4 month old) female mice (25), although we recently reported
102 that 13 months of un-weighted running may ultimately generate hypertrophy (14). Early
103 work from the Edgerton laboratory illustrated how gradually adding weight to a running
104 wheel over 8 weeks can elicit muscle hypertrophy in rats (23). It follows that by adding
105 resistance to a murine running wheel, one can leverage the mouse’s innate drive to run
106 and induce hypertrophy in multiple muscles. Initial attempts yielded some success in
107 generating hypertrophy across various muscles, but the constant loading of the wheel
108 ultimately results in reduced training volume at higher loads, thereby diminishing the
109 efficacy of this approach (7, 22, 31, 47, 52, 57). Our laboratory recently developed a
110 progressive weighted wheel running (PoWeR) strategy that circumvents this issue (13).
111 By loading standard running wheels progressively with 1 gram magnets situated
112 asymmetrically, which encourages repeated bouts of activity as opposed to continuous
113 running, adult female mice run 10-12 km/night for 8 weeks with up to 6 grams on the
114 wheel (~20% of body weight) (13); male mice will run similar volumes but slightly less,
115 while older mice (22-24 months) will run about half as much as younger mice
Mini Review
116 (unpublished data). Both the plantaris (glycolytic) and soleus (oxidative) muscles grow
117 15-30% according to whole muscle and muscle fiber cross-sectional area measures (13,
118 42), concomitant with a substantial glycolytic-to-oxidative fiber type shift and
119 myonuclear accretion; the gastrocnemius muscle also experiences fiber type-specific
120 growth (unpublished data). Furthermore, weighted wheel running can be adapted to
121 simulate an acute resistance exercise-like stimulus (11).
122 As with all non-surgical methods for inducing hypertrophy, the adaptations can be
123 reversible with detraining, thus allowing for study of the loss of adaptations in addition to
124 the gain of adaptations (13). Other advantages of PoWeR are that it does not involve
125 specialized equipment (only standard running wheels), requires minimal oversight, is
126 high-throughput (i.e. entire cohorts of mice can train at once), and induces robust
127 cardiac adaptations (13). PoWeR involves high volumes of moderate-velocity dynamic
128 contractions, is akin to resistive cycle training or concurrent training in humans (15, 41,
129 43), and simulates an “athlete-like” phenotype in mice (i.e. strength/power production
130 along with fatigue resistance). On balance, PoWeR is not strictly hypertrophic and may
131 not suit the needs of researchers interested in muscle growth alone; specifically, the
132 “hybrid” stimulus that features potentially large alterations in metabolism may
133 complicate the interpretation of results related to growth. The lack of control over
134 training volume may also present an issue; in our hands, female mice will consistently
135 run 10-12 km per night, but this may vary significantly from lab to lab and present
136 challenges for comparison across sex and age. Alternatively, varied running volume
137 within large cohorts can be leveraged to study the effects of training dosage on a
138 desired outcome (14). Collectively, PoWeR is a simple and effective means for inducing
139 hypertrophy across various muscles in mice, but should be used with the understanding
140 that training volume is high and that the stimulus is a combination of resistance and
141 endurance.
142 Weighted-Vest Motorized Wheel Running
143 Graber, Fendray, and Thompson in 2019 developed a method of training specifically to
144 enhance muscle power output (19), since the loss of whole muscle power-producing
145 capacity is a major contributor to age-related muscle dysfunction (46). This approach
Mini Review
146 involves outfitting mice with a bespoke weighted harness (vest) and locking them into a
147 custom motorized wheel for progressive training over the course of 12 weeks (19). The
148 stimulus involves a controlled dose of high-velocity dynamic contractions, administered
149 in ~60 second bouts to failure, that enhances muscle contractile function in younger
150 adult and aged mice (much like resistance training in humans). This strategy, which can
151 be considered involuntary since the mice are placed into a wheel that is then fastened
152 shut, also induces hypertrophy of the soleus and quadriceps muscles of the younger
153 mice. Advantages of this approach are that resistance (mass of the harness), intensity
154 (velocity of wheel), and frequency (days per week) can be tightly controlled and
155 individualized, making it similar to human resistance training. Aged mice can also
156 perform it (albeit with less hypertrophy than younger mice), and the quadriceps muscle
157 grows, which yields ~200-400 mg of tissue for diverse analyses from the same mouse.
158 The disadvantages are that it requires specialized equipment, is low-throughput, and is
159 only modestly hypertrophic in young plantaris muscles (historically a highly-studied
160 muscle in mice). While a very specialized mode of training, this is an effective approach
161 for inducing muscle hypertrophy (and power output) in the mouse hind limb via bouts of
162 loaded dynamic contraction.
163 High-Intensity Incline Treadmill Running
164 Simultaneous with the publication of PoWeR and weighted vest running to promote
165 hypertrophy in 2019, two laboratories developed involuntary high-intensity interval
166 inclined treadmill running protocols that involve high-velocity dynamic contractions to
167 induce muscle hypertrophy in mice (17, 51). These protocols generally entail increasing
168 speed and grade during 3 separate bouts per week over 8-16 weeks, which results in
169 increased muscle mass in lower extremity dorsi- and plantar-flexors in both young and
170 aged mice. This approach is advantageous because exercise volume, frequency, and
171 intensity can be closely monitored and controlled, and standard rodent treadmills can be
172 employed. Conversely, this method can cause undue stress on the mice (an electric
173 shock grid motivates the mice to run and excessive shocking occurs at higher
174 workloads), is labor-intensive and not high throughput, and is also associated with
175 endurance-type adaptations in addition to hypertrophic adaptations. High-intensity
Mini Review
176 treadmill running can induce hypertrophy across multiple muscle groups using
177 progressive bouts followed by rest, which is similar to human exercise, but may also be
178 considered a hybrid approach that develops an athlete-like phenotype, similar to
179 PoWeR.
180 Electrical Stimulation
181 A popular technique in rats (4, 58), involuntary electrical stimulation under anesthesia to
182 maximally activate lower-extremity muscles has been employed on a limited basis to
183 induce hypertrophy in mice (2, 21). This technique involves stimulation of the sciatic
184 nerve, causing the plantarflexor and dorsiflexor complexes to contract. The
185 plantarflexors are stronger, so they contract concentrically while the dorsiflexors
186 experience eccentric muscle action. Electrical stimulation generally results in
187 hypertrophy of the dorsiflexors and not the plantarflexors after 7 bouts over 2 weeks
188 (21), but has been reported to induce modest whole-muscle hypertrophy in the
189 gastrocnemius in healthy and cachectic mice after 14 sessions (53). The advantages of
190 this approach are that there is complete control over the training parameters and
191 exercise dosage (making load and work highly quantifiable), it can be modified to study
192 acute responses to eccentric loading (20, 45), it elicits modest but significant
193 hypertrophy in a matter of weeks (i.e. more rapidly than other models discussed here),
194 and can be deployed in unloaded, aged, and diseased populations where voluntary
195 training may not be possible. The disadvantages are that this approach requires
196 specialized equipment and expertise, is relatively labor intensive and low-throughput,
197 involves maximal motor unit recruitment for every contraction (which is unlike traditional
198 resistance training), necessitates frequent exposure of the mice to deep anesthesia,
199 and while a strong hypertrophic stimulus, the eccentric nature has the potential to
200 damage the dorsiflexors. Electrical stimulation is unique from the other training
201 modalities outlined in this review since it is eccentrically-driven and targets the
202 dorsiflexors (as opposed to plantarflexors), so it could be used in combination with other
203 training modes to explore hypertrophy mediated by a novel loading stimulus in muscles
204 of different function.
205
Mini Review
206 Squat-Like Exercise
207 Another popular technique for inducing hypertrophy in rats that is difficult to execute in
208 mice is squat-like exercise (9, 30, 34, 54). This approach involves operant conditioning
209 of the animal to push voluntarily against an object, often for a food reward. Recently, the
210 Yan lab cleverly and effectively adapted this model for usage in mice (10). Utilizing a
211 specialized cage that is substituted for a normal cage during the dark cycle, mice push
212 off on a ramp to displace a resistance-adjustable lid equipped with a magnetic sensor to
213 record activity. Pushing against the lid involves high volumes of concentric and
214 eccentric muscle actions that provide access to food. The motion required to move the
215 lid and access the food is similar to a squat motion in humans, and over the course of
216 eight weeks while performing ~400 repetitions per night with progressively increased
217 weight, hypertrophy of the soleus, plantaris, and gastrocnemius muscles was reported
218 (10). Importantly, mice did not eat less food nor lose weight during the training, which is
219 sometimes reported in other species using similar training models (9). This method
220 involves specialized equipment and daily replacement of the customized lid, making it
221 modestly labor intensive, and it is unknown whether mice under different conditions (e.g.
222 aged or diseased) can or would perform the squat activity. Otherwise, this model can be
223 adapted for an acute exercise bout (10), can be high-throughput, is primarily
224 hypertrophic (not hybrid), and is perhaps the closest available analog to “traditional”
225 concentric/eccentric resistance training in humans that involves voluntary repetitions
226 followed by rest (albeit at high frequency and volume).
227 Alternative Approaches
228 There are a few alternative approaches for resistance-training murine skeletal muscle.
229 Weighted ladder climbing, where a weight is attached to a mouse’s tail while it climbs a
230 vertical ladder, may result in modest growth of the plantaris muscle at the whole muscle
231 level, but not according to fiber cross-sectional area (28). A similar approach, unloaded
232 tower climbing, does not result in muscle hypertrophy (47). Being difficult to execute and
233 minimally effective, vertical climbing has not been widely adopted. Another interesting
234 strategy of resistance training in the mouse forelimb is voluntary burrowing through
235 resistant material within a burrowing tube, but this only increased grip strength and
Mini Review
236 muscle hypertrophy was not reported (47). These alternative approaches may be
237 appropriate for specific applications, but are not the most robust training modality for
238 inducing hypertrophy. One investigation reported on the efficacy of un-weighted vertical
239 hanging from a wire grid in mice as a method of isometric strength training (32). In this
240 model, mice hang from a metal wire grid for 3-minute sets repeated multiple times, 5
241 days per week. Fast-twitch muscle fiber diameter increased in the rectus femoris and
242 gastrocnemius after 10 weeks of training with this strategy, without a shift in muscle
243 fiber type composition (32). While inducing modest fiber type-specific hypertrophy in two
244 muscles, the training does not involve dynamic muscle action, which is a component of
245 traditional strength training in humans, and is very labor-intensive. A curious finding
246 from this investigation was that forced treadmill running 5 days per week was reported
247 to be equally, if not more hypertrophic at the muscle fiber level than the isometric
248 hanging. Introduced in 2013, wire hanging has not yet been widely adopted.
249 Conclusions
250 Selecting the best training modality for inducing hypertrophy in mice is context-specific
251 and highly contingent on the research question. There are clear tradeoffs between the
252 effective translatable strategies for inducing muscle hypertrophy: PoWeR, involuntary
253 weighted wheel running, involuntary incline treadmill running, involuntary electrical
254 stimulation, and voluntary squat-like exercise (summarized in Table 1). Worth
255 mentioning is that most models of murine hypertrophy have focused on muscle
256 adaptation resulting from ankle joint action, but adaptation in every muscle of the lower
257 limb is usually not characterized, nor are upper limb adaptations considered; in other
258 words, muscle and limb-specific adaptations for each modality deserve further
259 investigation. Enhanced translatability to humans, along with the ability to detrain
260 provide the opportunity to study muscle growth and de-loading while minimizing
261 confounding variables associated with a surgical approach, and can be combined with
262 genetically modified mice to provide detailed mechanistic insight into muscle mass
263 regulation.
264
Mini Review
265 References
266 1. Adams GR, and Bamman MM. Characterization and regulation of mechanical
267 loading induced compensatory muscle hypertrophy. Comprehensive Physiology 2:
268 2829-2870, 2012.
269 2. Al-Majid S, and McCarthy DO. Resistance exercise training attenuates wasting
270 of the extensor digitorum longus muscle in mice bearing the colon-26 adenocarcinoma.
271 Biological Research for Nursing 2: 155-166, 2001.
272 3. Allen DL, Harrison BC, Maass A, Bell ML, Byrnes WC, and Leinwand LA.
273 Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse.
274 Journal of Applied Physiology 90: 1900-1908, 2001.
275 4. Baar K, and Esser K. Phosphorylation of p70S6k correlates with increased
276 skeletal muscle mass following resistance exercise. American Journal of Physiology-
277 Cell Physiology 276: C120-C127, 1999.
278 5. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R,
279 Zlotchenko E, Scrimgeour A, Lawrence JC, and Glass DJ. Akt/mTOR pathway is a
280 crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.
281 Nature Cell Biology 3: 1014-1019, 2001.
282 6. Brooks MJ, Hajira A, Mohamed JS, and Alway SE. Voluntary wheel running
283 increases satellite cell abundance and improves recovery from disuse in gastrocnemius
284 muscles from mice. Journal of Applied Physiology 124: 1616-1628, 2018.
285 7. Call JA, Mckeehen JN, Novotny SA, and Lowe DA. Progressive resistance
286 voluntary wheel running in the mdx mouse. Muscle & Nerve 42: 871-880, 2010.
287 8. Chaillou T, Lee JD, England JH, Esser KA, and McCarthy JJ. Time course of
288 gene expression during mouse skeletal muscle hypertrophy. Journal of Applied
289 Physiology 115: 1065-1074, 2013.
290 9. Cholewa J, Guimarães Ferreira L, da Silva Teixeira T, Naimo MA, Zhi X, de
291 Sá RBDP, Lodetti A, Cardozo MQ, and Zanchi NE. Basic models modeling resistance
292 training: an update for basic scientists interested in study skeletal muscle hypertrophy.
293 Journal of Cellular Physiology 229: 1148-1156, 2014.
294 10. Cui D, Drake JC, Wilson RJ, Shute RJ, Lewellen B, Zhang M, Zhao H, Sabik
295 OL, Onengut S, Berr SS, and Yan Z. A novel voluntary weightlifting model in mice
296 promotes muscle adaptation and insulin sensitivity with simultaneous enhancement of
297 autophagy and mTOR pathway. The FASEB Journal 34(6): 7330-7344, 2020.
298 11. D'Hulst G, Palmer AS, Masschelein E, Bar-Nur O, and De Bock K. Voluntary
299 resistance running as a model to induce mTOR activation in mouse skeletal muscle.
300 Frontiers in Physiology 10: 1271, 2019.
301 12. Dreyer HC, Fujita S, Cadenas JG, Chinkes DL, Volpi E, and Rasmussen BB.
302 Resistance exercise increases AMPK activity and reduces 4E BP1 phosphorylation
303 and protein synthesis in human skeletal muscle. The Journal of Physiology 576: 613-
304 624, 2006.
305 13. Dungan CM, Murach KA, Frick KK, Jones SR, Crow SE, Englund DA,
306 Vechetti Jr IJ, Figueiredo VC, Levitan BM, Satin J, McCarthy JJ, and Peterson CA.
307 Elevated myonuclear density during skeletal muscle hypertrophy in response to training
308 is reversed during detraining. American Journal of Physiology-Cell Physiology 316:
309 C649-C654, 2019.
10
Mini Review
310 14. Englund DA, Murach KA, Dungan CM, Figueiredo VC, Vechetti Jr IJ,
311 Dupont-Versteegden EE, McCarthy JJ, and Peterson CA. Depletion of resident
312 muscle stem cells negatively impacts running volume, physical function and muscle
313 hypertrophy in response to lifelong physical activity. American Journal of Physiology-
314 Cell Physiology 318(6): C1178-C1188, 2020.
315 15. Fry CS, Noehren B, Mula J, Ubele MF, Westgate PM, Kern PA, and Peterson
316 CA. Fibre type-specific satellite cell response to aerobic training in sedentary adults.
317 Journal of Physiology 592: 2625-2635, 2014.
318 16. Fukuda S, Kaneshige A, Kaji T, Noguchi Y-t, Takemoto Y, Zhang L,
319 Tsujikawa K, Kokubo H, Uezumi A, and Maehara K. Sustained expression of HeyL is
320 critical for the proliferation of muscle stem cells in overloaded muscle. eLife 8: 2019.
321 17. Goh Q, Song T, Petrany MJ, Cramer AA, Sun C, Sadayappan S, Lee S-J, and
322 Millay DP. Myonuclear accretion is a determinant of exercise-induced remodeling in
323 skeletal muscle. eLife 8: e44876, 2019.
324 18. Goldberg AL. Work-induced growth of skeletal muscle in normal and
325 hypophysectomized rats. American Journal of Physiology-Legacy Content 213: 1193-
326 1198, 1967.
327 19. Graber TG, Fandrey KR, and Thompson LV. Novel individualized power
328 training protocol preserves physical function in adult and older mice. GeroScience 41:
329 165-183, 2019.
330 20. Hardee JP, Counts BR, Gao S, VanderVeen BN, Fix DK, Koh HJ, and Carson
331 JA. Inflammatory signalling regulates eccentric contraction induced protein synthesis in
332 cachectic skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle 9: 369-383,
333 2018.
334 21. Hardee JP, Mangum JE, Gao S, Sato S, Hetzler KL, Puppa MJ, Fix DK, and
335 Carson JA. Eccentric contraction-induced myofiber growth in tumor-bearing mice.
336 Journal of Applied Physiology 120: 29-37, 2016.
337 22. Ishihara A, Hirofuji C, Nakatani T, Itoh K, Itoh M, and Katsuta S. Effects of
338 running exercise with increasing loads on tibialis anterior muscle fibres in mice.
339 Experimental Physiology 87: 113-116, 2002.
340 23. Ishihara A, Roy RR, Ohira Y, Ibata Y, and Edgerton VR. Hypertrophy of rat
341 plantaris muscle fibers after voluntary running with increasing loads. Journal of Applied
342 Physiology 84: 2183-2189, 1998.
343 24. Iwata M, Englund DA, Wen Y, Dungan CM, Murach KA, Vechetti IJ, Mobley
344 CB, Peterson CA, and McCarthy JJ. A novel tetracycline-responsive transgenic
345 mouse strain for skeletal muscle-specific gene expression. Skeletal Muscle 8: 33, 2018.
346 25. Jackson JR, Kirby TJ, Fry CS, Cooper RL, McCarthy JJ, Peterson CA, and
347 Dupont-Versteegden EE. Reduced voluntary running performance is associated with
348 impaired coordination as a result of muscle satellite cell depletion in adult mice. Skeletal
349 Muscle 5: 41, 2015.
350 26. James N. Compensatory muscular hypertrophy in the extensor digitorum longus
351 muscle of the mouse. Journal of Anatomy 122: 121, 1976.
352 27. Jorgenson KW, and Hornberger TA. The overlooked role of fiber length in
353 mechanical load-induced growth of skeletal muscle. Exercise and Sport Sciences
354 Reviews 47: 258-259, 2019.
11
Mini Review
355 28. Khamoui AV, Park B-S, Kim D-H, Yeh M-C, Oh S-L, Elam ML, Jo E, Arjmandi
356 BH, Salazar G, and Grant SC. Aerobic and resistance training dependent skeletal
357 muscle plasticity in the colon-26 murine model of cancer cachexia. Metabolism 65: 685-
358 698, 2016.
359 29. Kirby TJ, McCarthy JJ, Peterson CA, and Fry CS. Synergist ablation as a
360 rodent model to study satellite cell dynamics in adult skeletal muscle. Skeletal Muscle
361 Regeneration in the Mouse: Methods and Protocols 43-52, 2016.
362 30. Klitgaard H. A model for quantitative strength training of hindlimb muscles of the
363 rat. Journal of Applied Physiology 64: 1740-1745, 1988.
364 31. Konhilas JP, Widegren U, Allen DL, Paul AC, Cleary A, and Leinwand LA.
365 Loaded wheel running and muscle adaptation in the mouse. American Journal of
366 Physiology-Heart and Circulatory Physiology 289: H455-H465, 2005.
367 32. Krüger K, Gessner DK, Seimetz M, Banisch J, Ringseis R, Eder K,
368 Weissmann N, and Mooren FC. Functional and muscular adaptations in an
369 experimental model for isometric strength training in mice. PloS One 8: 2013.
370 33. Li P, Akimoto T, Zhang M, Williams RS, and Yan Z. Resident stem cells are
371 not required for exercise-induced fiber-type switching and angiogenesis but are
372 necessary for activity-dependent muscle growth. American Journal of Physiology-Cell
373 Physiology 290: C1461-C1468, 2006.
374 34. Lowe DA, and Alway SE. Animal models for inducing muscle hypertrophy: are
375 they relevant for clinical applications in humans? Journal of Orthopaedic & Sports
376 Physical Therapy 32: 36-43, 2002.
377 35. McCarthy JJ, and Esser KA. MicroRNA-1 and microRNA-133a expression are
378 decreased during skeletal muscle hypertrophy. Journal of Applied Physiology 102: 306-
379 313, 2007.
380 36. McCarthy JJ, Mula J, Miyazaki M, Erfani R, Garrison K, Farooqui AB,
381 Srikuea R, Lawson BA, Grimes B, Keller C, Van Zant G, Campbell KS, Esser KA,
382 Dupont-Versteegden EE, and Peterson CA. Effective fiber hypertrophy in satellite
383 cell-depleted skeletal muscle. Development 138: 3657-3666, 2011.
384 37. McCarthy JJ, Srikuea R, Kirby TJ, Peterson CA, and Esser KA. Inducible Cre
385 transgenic mouse strain for skeletal muscle-specific gene targeting. Skeletal Muscle 2:
386 8, 2012.
387 38. McPherron AC, Lawler AM, and Lee S-J. Regulation of skeletal muscle mass in
388 mice by a new TGF-beta superfamily member. Nature 387: 83-90, 1997.
389 39. McPherron AC, and Lee S-J. Double muscling in cattle due to mutations in the
390 myostatin gene. Proceedings of the National Academy of Sciences 94: 12457-12461,
391 1997.
392 40. Mobley CB, Vechetti Jr IJ, Valentino TR, and McCarthy JJ. Cores of
393 Reproducibility in Physiology (CORP): Using transgenic mice to study skeletal muscle
394 physiology. Journal of Applied Physiology 128(5): 1227-1239, 2020.
395 41. Murach KA, and Bagley JR. Skeletal muscle hypertrophy with concurrent
396 exercise training: Contrary evidence for an interference effect. Sports Medicine 46:
397 1029-1039, 2016.
398 42. Murach KA, Dungan CM, Peterson CA, and McCarthy JJ. Muscle fiber
399 splitting is a physiological response to extreme loading in animals. Exercise and Sport
400 Sciences Reviews 47: 108-115, 2019.
12
Mini Review
401 43. Murach KA, Walton RG, Fry CS, Michaelis SL, Groshong JS, Finlin BS, Kern
402 PA, and Peterson CA. Cycle training modulates satellite cell and transcriptional
403 responses to a bout of resistance exercise. Physiological Reports 4: e12973, 2016.
404 44. Murach KA, White SH, Wen Y, Ho A, Dupont-Versteegden EE, McCarthy JJ,
405 and Peterson CA. Differential requirement for satellite cells during overload-induced
406 muscle hypertrophy in growing versus mature mice. Skeletal Muscle 7: 2017.
407 45. O’Neil TK, Duffy L, Frey J, and Hornberger T. The role of phosphoinositide 3
408 kinase and phosphatidic acid in the regulation of mammalian target of rapamycin
409 following eccentric contractions. The Journal of Physiology 587: 3691-3701, 2009.
410 46. Reid KF, and Fielding RA. Skeletal muscle power: A critical determinant of
411 physical functioning in older adults. Exercise and Sport Sciences Reviews 40: 4, 2012.
412 47. Roemers P, Mazzola P, De Deyn P, Bossers W, van Heuvelen M, and van
413 der Zee E. Burrowing as a novel voluntary strength training method for mice: a
414 comparison of various voluntary strength or resistance exercise methods. Journal of
415 Neuroscience Methods 300: 112-126, 2018.
416 48. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN,
417 Yancopoulos GD, and Glass DJ. Mediation of IGF-1-induced skeletal myotube
418 hypertrophy by PI (3) K/Akt/mTOR and PI (3) K/Akt/GSK3 pathways. Nature Cell
419 Biology 3: 1009-1013, 2001.
420 49. Roth SM, Martel GF, Ferrell RE, Metter EJ, Hurley BF, and Rogers MA.
421 Myostatin gene expression is reduced in humans with heavy-resistance strength
422 training: A brief communication. Experimental Biology and Medicine 228: 706-709, 2003.
423 50. Roy RR, and Edgerton V. Response of mouse plantaris muscle to functional
424 overload: comparison with rat and cat. Comparative Biochemistry and Physiology Part
425 A: Physiology 111: 569-575, 1995.
426 51. Seldeen KL, Lasky G, Leiker MM, Pang M, Personius KE, and Troen BR.
427 High intensity interval training improves physical performance and frailty in aged mice.
428 The Journals of Gerontology: Series A 73: 429-437, 2018.
429 52. Soffe Z, Radley-Crabb HG, McMahon C, Grounds MD, and Shavlakadze T.
430 Effects of loaded voluntary wheel exercise on performance and muscle hypertrophy in
431 young and old male C57Bl/6J mice. Scandinavia Journal of Medicine and Science in
432 Sports 26: 172-188, 2016.
433 53. Tatebayashi D, Himori K, Yamada R, Ashida Y, Miyazaki M, and Yamada T.
434 High-intensity eccentric training ameliorates muscle wasting in colon 26 tumor-bearing
435 mice. PloS One 13: 2018.
436 54. Timson BF. Evaluation of animal models for the study of exercise-induced
437 muscle enlargement. Journal of Applied Physiology 69: 1935-1945, 1990.
438 55. Verbrugge SA, Schönfelder M, Becker L, Yaghoob Nezhad F, Hrabě de
439 Angelis M, and Wackerhage H. Genes whose gain or loss-of-function increases
440 skeletal muscle mass in mice: a systematic literature review. Frontiers in Physiology 9:
441 553, 2018.
442 56. von Walden F, Rea M, Mobley CB, Fondufe-Mittendorf Y, McCarthy JJ,
443 Peterson CA, and Murach KA. The myonuclear DNA methylome in response to an
444 acute hypertrophic stimulus. Epigenetics https://doi.org/10.1080/15592294.2020.
445 1755581. 2020.
446
13
Mini Review
447 57. White Z, Terrill J, White RB, McMahon C, Sheard P, Grounds MD, and
448 Shavlakadze T. Voluntary resistance wheel exercise from mid-life prevents sarcopenia
449 and increases markers of mitochondrial function and autophagy in muscles of old male
450 and female C57BL/6J mice. Skeletal Muscle 6: 45, 2016.
451 58. Wong T, and Booth FW. Skeletal muscle enlargement with weight-lifting
452 exercise by rats. Journal of Applied Physiology 65: 950-954, 1988.
453 59. You J-S, Dooley MS, Kim C-R, Kim E-J, Xu W, Goodman CA, and
454 Hornberger TA. A DGKζ-FoxO-ubiquitin proteolytic axis controls fiber size during
455 skeletal muscle remodeling. Science Signaling 11: eaao6847, 2018.
456 60. You J-S, McNally RM, Jacobs BL, Privett RE, Gundermann DM, Lin K-H,
457 Steinert ND, Goodman CA, and Hornberger TA. The role of raptor in the mechanical
458 load-induced regulation of mTOR signaling, protein synthesis, and skeletal muscle
459 hypertrophy. The FASEB Journal 33: 4021-4034, 2019.
460
461
14
Non-Standard Volume Fiber-Type
Model Voluntary Throughput Hypertrophied Muscle(s) Fiber Size Refs
Equipment Control Shift
Progressive Plantaris (15%) ↑ (17%) Yes Dungan 2019
Weighted Wheel Yes No No High (oxidative)
Running (8 wks) Soleus (NR) ↑ (22%) NR Murach 2019
Weighted-Vest
Soleus (15%)
Motorized Wheel No Yes Yes Low ↑ (7-10%, Soleus) NR Graber 2019
Quadriceps (22%)
Running (12 wks)
Aged mice: Soleus (29%),
↑ (18%, glycolytic TA) Yes Seldeen 2018
High-Intensity Incline EDL (13%)
Low- (oxidative)
Treadmill Running No Yes Yes
Moderate
(8-16 wks) Gastrocnemius, Quadriceps,
↑ NR Goh 2019
TA, EDL (10-20%)#
TA (7%) ↑ NR Hardee 2016
Electrical Stimulation
No Yes Yes Low
(≤4 wks)
Gastrocnemius (5%) NR NR Tatebayashi 2018
Squat-Like Exercise Soleus, Plantaris,
Yes Yes No High NR NR Cui 2020
(8 wks) Gastrocnemius (10-20%)#
NR – Not Reported, EDL – Extensor Digitorum Longus, TA – Tibialis Anterior
Data from young adult mice are shown in the table (except where noted), and values reported are statistically significant, # estimated from figures

Resistance Training in Mice.

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Resistance Training in Mice.

Uploaded by

Copyright:

Available Formats

1 Title Making Mice Mighty: Recent Advances in Translational Models of

2 Load-Induced Muscle Hypertrophy

3 Authors Kevin A. Murach1,2*, John J. McCarthy1,3, Charlotte A. Peterson1,2,3,

19 *Correspondence Kevin A. Murach, PhD

65 To identify targets associated with load-mediated muscle hypertrophy, as well as test

86 Very recently, an explosion of alternatives to synergist ablation for enhancing muscle

96 Progressive Weighted Wheel Running

142 Weighted-Vest Motorized Wheel Running

163 High-Intensity Incline Treadmill Running

180 Electrical Stimulation

206 Squat-Like Exercise

227 Alternative Approaches

You might also like